Cephalosporins

ABSTRACT

A compound selected from the group consisting of a syn isomer of a compound of the formula ##STR1## in the R or S form or in the form of a R, S mixture wherein the various substituents are defined as in the specification and their non-toxic, pharmaceutically acceptable acid addition salts having anti-bacterial activity.

PRIOR APPLICATIONS

This application is a division of U.S. patent application Ser. No.987,007 pending filed Dec. 7, 1992 which is a continuation-in-part ofU.S. patent application Ser. No. 715,510 filed Jun. 14, 1991, nowabandoned.

STATE OF THE ART

Related prior art includes U.S. Pat. Nos. 4,486,586; 4,751,295 and4,921,850, PCT application No. WO 87-03875 and European PatentApplications Nos. 0,315,518; NO. 0,333,154 and No. 0,266,060.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel syn isomers of thecompounds of formula I and their non-toxic, pharmaceutically acceptableacid addition salts and a novel process and novel intermediate for theirpreparation.

It is another object of the invention to provide novel anti-bacterialcompositions and a novel method of combatting bacterial infections inwarm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of the syn isomer of a compound of the formula ##STR2## inthe R or S form or in the form of an R, S mixture wherein R₁ is selectedfrom the group consisting of ##STR3## in the quaternary ammonium form,##STR4## R and R' are individually selected from the group consisting ofhydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms,halogen, CO₂ --Q, ##STR5## CH₂ --SQ, Q and Q' are individually hydrogenor alkyl of 1 to 4 carbon atoms, P, P' and P" are individually alkyl of1 to 4 carbon atoms optionally substituted by one of the substituentsfor R and R', the dotted line indicating that P and P' can optionallyform with the nitrogen atom to which they are linked a heterocycle with5 or 6 links, R_(b) and R_(c) are individually hydrogen or acyl, A andA' are individually selected from the group consisting of hydrogen, anequivalent of an alkali metal, an alkaline earth metal, magnesium,ammonium and an amine organic base or A and A' are the remainder of aneasily cleavable ester group or CO₂ A is CO₂ ⁻, and the wavy lineindicates that CH₂ R₁ is in the E or Z position and their non-toxic,pharmaceutically acceptable acid addition salts.

Examples of alkyl of 1 to 4 carbon atoms are methyl, ethyl, propyl,isopropyl and linear or branched butyl. When P and P' form a heterocyclewith the nitrogen to which they are attached, it is preferablypyrrolidino, piperidino or morpholino.

When R_(b) and/or R_(c) is acyl, it may be acetyl, propionyl or benzoyl,preferably acetyl. However, R_(b) and R_(c) are preferably hydrogen.

Among the preferred values of A and A' are an equivalent of sodium,potassium, lithium, calcium, magnesium or ammonium. Examples of theorganic bases are methylamine, propylamine, trimethylamine,diethylamine, triethylamine, N,N-dimethylethanolamine,tris[(hydroxymethyl)-amino]-methane, ethanolamine, pyridine, picoline,dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine,histidine and N-methylglucamine.

Examples of easily cleavable ester groups of A and A' are methoxymethyl,ethoxymethyl, isopropyloxymethyl, alpha-methoxy ethyl,methyl-thiomethyl, ethylthiomethyl, isopropylthiomethyl,pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl,isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl,tert-butylcarbonyloxymethyl, hexadecanoyloxymethyl, propionyloxyethyl,isovaleryloxyethyl, 1-acetyloxyhexyl, 1-propionyloxyethyl,1-butyryloxyethyl, 1-tert-butylcarbonyloxyethyl, 1-acetyloxypropyl,1-hexadecanoyloxyethyl, 1-propionyloxypropyl, 1-methoxycarbonyloxyethyl,methoxycarbonyloxymethyl, 1-acetyloxybutyl, 1-acetyloxyhexyl,1-acetyloxyheptyl, phthalidyl, 5,6-dimethoxyphthalidyl,tert-butylcarbonylmethyl, allyl, 2-chloroallyl, methoxycarbonylmethyl,benzyl and tert-butyl.

Other ester groups for A and A' are methoxyethoxymethyl,dimethylaminoethyl, cyanomethyl, tert-butoxycarbonylmethyl,2,2-ethylenedioxyethyl, cyanoethyl, 2,2-dimethoxyethyl,2-chloroethoxymethyl-2-hydroxyethoxy-ethyl, 2,3-epoxypropyl,3-dimethylamino, 2-hydroxypropyl, 2-hydroxyethyl,2-methylaminoethoxymethyl, 2-aminoethoxymethyl,3-methoxy-2,4-thiadiazol-5-yl,2-tetrahydropyrannyl-1-methoxy-1-methylethyl, 2-hydroxy-1-methylethyl,isopropyl, carbamoylmethyl, chloromethyl, 2-chloroethyl, acetylmethyl,2-methylthioethyl and thiocyanatomethyl.

Among the other esters groups for A and A' are2-chloro-1-acetyloxyethyl, 2-bromo-1-acetyloxyethyl,2-fluoro-1-acetyloxyethyl, 2-methoxy-1-acetyloxyethyl,2-methyl-1-acetyloxypropyl, 1-methyl-1-acetyloxyethyl,1-methoxyacetyloxyethyl, 1-acetylcarbonyloxyethyl,1-hydroxyacetyloxyethyl, 1-formylcarbonyloxyethyl,1-(2-thienyl)-carbonyloxyethyl, 1-(2-furyl)-carbonyloxyethyl,1-(5-nitro-2-furyl)-carbonyloxyethyl, 1-(2-pyrrolyl)-carbonyloxyethyl,1-propionyloxycarbonyloxy)-ethyl, 1-(propyloxycarbonyloxy)-ethyl,1-(isopropyloxycarbonyloxy)-ethyl, 1-(methoxyethoxycarbonyloxy)-ethyl,1-allyloxycarbonyloxy)-ethyl, isopropyloxycarbonyl-methyl,1-[(2,3-epoxypropyl)-oxycarbonyloxy]-ethyl,1-[(2-furyl)-methoxycarbonyloxy]-ethyl,1-(2-fluoro-ethyl)-oxycarbonyloxyethyl, 1-(methoxycarbonyloxy)-propyl,1-(methoxycarbonyloxy)-1-methyl-ethyl,(methoxycarbonyloxy)-chloromethyl,1-methoxy-1-(methoxycarbonyloxy)-2-chloroethyl,1-(methoxycarbonyloxy)-2-methoxy-ethyl, 1-(methoxycarbonyloxy)-allyl anda remainder of the formula ##STR6##

Examples of the acids for the formation of the non-toxic,pharmaceutically acceptable acid addition salts are inorganic acids suchas hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid and sulfuric acid and organic acids such as formic acid,acetic acid, propionic acid, trifluoroacetic acid, benzoic acid,tartaric acid, fumaric acid, maleic acid, methane sulfonic acid, benzenesulfonic acid and p-toluene sulfonic acid.

Preferably A' is hydrogen or sodium, most preferably hydrogen and --COOAis --COO⁻. The expression "in the form of quaternary ammonium" meansthat R₁ is linked by the nitrogen or one of the nitrogen atoms that itcontains.

Among the preferred compounds of formula I are those wherein R₁ isselected from the group consisting of ##STR7##

In a more preferred group consisting of formula I, R₁ is selected fromthe group consisting of ##STR8##

Among the specific preferred compounds of formula I are

a) [6R-[3(E),6α,7β-(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thiazolo-[4,5-c]-pyridiniumin the R or S form or in the form of an R, S mixture and in the form ofan internal salt or a salt with alkali metals, alkaline earth metals,magnesium, ammonia, amine organic bases, acids and its easily cleavableesters,

b) [6R-[3(E),6α,7β-(Z)]]7-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumis the R or S form or in the form of an R, S, mixture and in the form ofan internal salt or a salt with alkali metals, alkaline earth metals,magnesium, ammonia, amine organic bases, acids and its easily cleavableesters and particularly in the S form,

c) [6R-[3E),6α,7β-(Z)]]-2-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]isoquinoliniumin the R or S form or in the form of an R, S mixture and in the form ofan internal salt or a salt with alkali metals, alkaline earth metals,magnesium, ammonia, amine organic bases, acids and its easily cleavableesters,

d) [6R-[3(E),6α,7β-(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxypheny)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-1-methylpyrrolidinium in the R or S form or the form of an R, S mixture and inthe form of an internal salt or a salt with alkali metals, alkalineearth metals, magnesium, ammonia, amine organic bases, acids and itseasily cleavable esters,

e) [6R-[3(E), 6α,7β-(Z)]]1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-6,7-dihydro-5H-pyridiniumin the R or S form or in the form of an R, S mixture and in the form ofan internal salt or a salt with alkali metals, alkaline earth metals,magnesium, ammonia, amine organic bases, acids and its easily cleavableesters and

f) [6R-[3(E),6,7-(Z)]]-N-(2-amino-2-oxoethyl)-3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-N,N-dimethyl-2propen-1-aminiumin the R or S form or in the form of an R, S mixture and in the form ofan internal salt or salt with alkali metals, alkaline earth metals,magnesium, ammonia, amine organic bases, acids and its easily cleavableesters.

It is understood that the products of formula I can exist either in theform indicated by formula I or in the form of products of the formula##STR9## in which A, A', R₁, R_(b) and R_(c) have the above meanings.

The novel process of the invention for the preparation of a compound offormula I comprises reacting a compound of the formula ##STR10## racemicor optically active syn isomer or a functional derivative thereof inwhich R_(a) is hydrogen or a protective group of the amino, R_(b) andR_(c) are individually hydrogen or a protective group of the hydroxyl,R_(d) is hydrogen or the remainder of an easily eliminatable ester groupwith a compound of the formula ##STR11## in which Hal is halogen, A" ishydrogen or the remainder of an easily eliminatable ester group and thewavy line indicates that the CH₂ Hal can be found in the E or Z positionto obtain a compound of the formula ##STR12## reacting the latter with areagent capable of introducing R₁ to obtain a compound of the formulawhich is optionally separated into its E or Z isomers or the Z isomersare converted into E isomers and subjecting the products of formula V,if necessary or if desired, to one or more of the following reactions inany order:

a) cleaving by hydrolysis or by the action of thiourea of all or part ofthe ester groups or protective groups of the amino or the hydroxyl,

b) esterification or salification of the carboxylic(s) by a base,

c) salification of the amino by an acid,

d) separation of the products in the form of an R, S mixture into R orS.

Reagents capable of introducing R₁ include either when R₁ is aquaternary ammonium, a reagent composed of the R₁ itself, this not beingin the form of quaternary ammonium. If one wishes to introduce apyridinium, the operation will be done with pyridine, or when R₁ is##STR13## a reagent corresponding respectively to ##STR14## orpreferably its sodium salt.

Among the preferred reagents are those of the formulae ##STR15##

In addition to the groups mentioned above, the easily eliminable estersgroups of A" and R_(d) may be, for example, the ester formed with thefollowing; butyl, isobutyl, tert-butyl, pentyl, hexyl, acetoxymethyl,propionyloxymethyl, butyryloxymethyl, valeryloxymethyl,pivaloyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl and2-butyryloxyethyl or 2-iodoethyl, 2,2,2-trichloroethyl, vinyl, allyl,ethynyl, propynyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl,trityl, diphenylmethyl, 3,4-dimethyloxyphenyl, phenyl, 4-chlorophenyl,tolyl, tert-butylphenyl. Diphenylmethyl is preferred for R_(d) and4-methoxybenzyl or diphenylmethyl is preferred for A".

The protective group of the amino radical which is R_(a) can be alkyl of1 to 6 carbon atoms such as preferably, tert-butyl or tert-amyl, R_(a)can also be aliphatic aromatic or heterocyclic acyl or carbamoyl. Thelower alkanoyl groups can be formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl.

R_(a) can also be lower alkoxy or cycloalkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,1-cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl,tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, benzoyl,toluolyl, naphthoyl, phthaloyl, mesyl, phenylacetyl, phenylpropionyl andaralkoxycarbonyl such as benzyloxycarbonyl.

The acyl groups can be substituted by chlorine, bromine, iodine orfluorine such as chloroacetyl, dichloroacetyl, trichloroacetyl,bromoacetyl or trifluoroacetyl.

R_(a) can also be lower aralkyl such as benzyl, 4-methoxybenzyl,phenethyl, trityl, 3,4-dimethoxybenzyl or benzhydryl or haloalkyl suchas trichloroethyl or chlorobenzoyl, p-nitrobenzoyl, p-tertbutylbenzoyl,phenoxyacetyl, caprylyl, n-decanoyl, acryloxy ortrichloroethoxycarbonyl.

R_(a) can also be methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl aswell as the corresponding thiocarbamoyls. Trityl is preferred. The abovelist is not limitative and it is obvious that other amine protectivegroups, particularly groups known in the chemistry of peptides, can alsobe used.

The protective group of the hydroxyl which can be R'_(b) and R'_(c) canbe chosen from the list below: R'_(b) and R'_(c) can be acyl such asformyl, acetyl, propionyl, chloroacetyl, bromoacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,benzoylformyl, p-nitrobenzoyl or ethoxycarbonyl, methoxycarbonyl,propoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl,tert-butoxycarbonyl, 1-cyclopropylethoxycarbonyl, tetrahydropyrannyl,tetrahydrothiopyrannyl, methoxytetrahydropyrannyl, trityl, benzyl,4-methoxybenzyl, benzyhydryl, trichloroethyl, 1-methyl-1-methoxyethyl,phthaloyl. Other acyls are butyryl, isobutyryl, valeryl, isovaleryl,oxalyl, succinyl and pivaloyl.

Also useful are phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl,p-nitrobenzoyl, p-tert-butylbenzoyl, caprylyl, acryloyl,methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl or alkoxyalkoxymethyl such as methoxyethoxymethyl.

OR'_(b) or OR'_(c) can also form with the phenyl to which they areattached groups such as ##STR16## Methoxyethoxymethyl is preferred forsubstituents R'_(b) and R'_(c).

In a method for implementing the process, a functional derivative of theproduct of formula II is reacted which functional derivative can be ahalide, a symmetrical or mixed anhydride, an amide, an azide or anactivated ester. Examples of a mixed anhydride are those formed withisobutyl chloroformate and with pivaloyl chloride and thecarboxylic-sulfonic mixed anhydrides formed, with p-toluene sulfonylchloride,

An example of an activated ester is the ester formed with2,4-dinitrophenol and with hydroxybenzothiazole. An example of thehalide is acid chloride or bromide. The anhydride can be formed in situby reaction of N,N'-disubstituted carbodiimide such asN,N-dicyclohexylcarbodiimide.

The acylation reaction preferably takes place in an organic solvent suchas methylene chloride but other solvents such as tetrahydrofuran,chloroform or dimethylformamide may be used. When an acid halide isused, generally when an acid halide molecule is released during thereaction, the reaction is preferably carried out in the presence of abase such as sodium hydroxide, potassium hydroxide, sodium or potassiumcarbonate and bicarbonate, sodium acetate, triethylamine, pyridine,morpholine or N-methylmorpholine. The reaction temperature is generallylower or equal to ambient temperature.

Also a product of formula II can be reacted directly with a product offormula III in the presence of a carbodiimide such asdiisopropylcarbodiimide.

The reaction of the reagents capable of introducing R₁ into the productof formula IV is carried out under the following conditions: When Hal ischlorine, a substitution of the chlorine by iodine in the presence ofsodium iodide can be carried out in situ or separately and then thedesired reagent is added, either in the presence or not of an organicsolvent such as acetonitrile or tetrahydrofuran. The desired reagent canalso be reacted in the presence of silver tetrafluoroborate on theproduct of formula IV in which Hal is chlorine.

The isomerism of the products of formula V can be different than that ofthe products of formula IV at the start. In the case where the Z isomeris isolated, this isomer can be converted into the E isomer by knownmethods, preferably by the action of iodine.

Depending upon the values of R_(a), R'_(b), R'_(c), R_(d) and A", theproducts of formula V can or cannot constitute the products of formulaI. The products of formula V constitute the products of formula I whenR_(a) is hydrogen, when R'_(b) and R'_(c) are not a protective group ofthe hydroxyl that one wishes to eliminate, namely when R'_(b) and/orR'_(c) is acyl and when R_(d) and A" are not among the easily cleavableester groups, one of those that one would wish to eliminate.

In other cases, the action on the product of the formula V of one ormore hydrolysis agents, hydrogenolysis agents or thiourea has the objectof eliminating R_(a) when it is a protective group of the amino, ofeliminating the R'_(b) and R'_(c) when these are protective groups ofthe hydroxyl and/or of eliminating the R_(d) and A" when these are amongthe easily cleavable esters of those that one wishes to eliminate.

However, it is of course possible to eliminate R_(a), R'_(b) and R'_(c)without touching substituents R_(d) and A" when these must be preserved.This is the case, for example, when A" is an ester group that is to bepreserved such as propionyloxymethyl. The nature of the reagents broughtinto play in such a case is well known to one skilled in the art. Forexample, a description of the various elimination methods of thedifferent protective groups will be found in French Patent ApplicationNo. 2,499,995.

Given that the preferred protective groups used are trityl for R_(a),methoxyethoxymethyl for R'_(b) and R'_(c), diphenylmethyl for R_(d) and4-methoxybenzyl or diphenylmethyl for A", trifluoroacetic acid without asolvent or in a solvent such as anisole or a mixture of solvents such asanisole/methylene chloride is preferably used. A salt is then obtainedwith trifluoroacetic acid and return to the free base can be effected bythe action of a base such as triethylamine carbonate.

The salification of the products can be carried out according to usualmethods. Salification can be obtained by the action of a mineral basesuch as sodium hydroxide or potassium hydroxide, sodium or potassiumcarbonate or bicarbonate on a product in acid form or on a solvate, forexample, the ethanolic solvate or hydrate of this acid. Mineral acidsalts such as trisodium phosphate can also be used as well as organicacid salts.

Examples of organic acid salts are sodium salts of aliphatic, linear orbranched, saturated or unsaturated carboxylic acids with 1 to 18 carbonatoms and preferably with 2 to 10 carbon atoms. The aliphatic chains ofthese acids can be interrupted by one or more heteroatoms such as oxygenor sulfur or substituted by aryl such as phenyl, thienyl, furyl, by oneor more hydroxyls or by one or more halogens such as fluorine, chlorineor bromine, preferably chlorine, by one or more carboxylic or loweralkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl orpropyloxycarbonyl, by one or more aryloxys, preferably phenoxy.

Furthermore, as organic acids, sufficiently soluble aromatic acids canbe used such as substituted benzoic acids, preferably substituted bylower alkyl radicals. Examples of such organic acids are formic acid,acetic acid, butyric acid, adipic acid, isobutyric acid, n-caproic acid,isocaproic acid, chloropropionic acid, crotonic acid, phenylacetic acid,2-thienylacetic acid, 3-thienyl-acetic acid, 4-ethylphenylacetic acid,glutaric acid, the monoethylic ester of adipic acid, hexanoic acid,heptanoic acid, decanoic acid, oleic acid, stearic acid, palmitic acid,3-hydroxypropionic acid, 3-methoxypropionic acid, 3-methoxythiobutyricacid, 4-chlorobutyric, 4-phenylbutyric acid, 3-phenoxybutyric acid,4-ethylbenzoic acid, 1-propylbenzoic acid. However, sodium acetate,sodium 2-ethyl hexanoate or sodium diethyl acetate and preferably usedas sodium salts.

Salification can also be obtained by the action of an organic base suchas triethylamine, diethylamine, trimethylamine, propylamine,N,N-dimethylethanolamine, tris[(hydroxymethyl)-amino]-methane,methylamine, ethanolamine, pyridine, picoline, dicyclohexyl amine,morpholine and benzylamine or by the action of arginine, lysine,procaine, histidine, N-methyl glucamine. This salification is preferablycarried out in a solvent or a mixture of solvents such as water, ethylether, methanol, ethanol or acetone.

The salts are obtained in amorphous of crystallized form according tothe reaction conditions employed. Crystallized salts are preparedpreferably by reacting free acids with one of the salts of the aliphaticcarboxylic acids mentioned above, preferably with sodium acetate. Thesalification of products by mineral or organic acids is carried out inthe usual conditions.

The optional esterification of products is carried out under standardconditions, generally by reacting the acid of formula I or a functionalderivative thereof with a derivative of the formula

    Z--Re

in which Z is hydroxyl or halogen such as chlorine, bromine, iodine andRe is the ester group to be introduced, a non-exhaustive list of whichgroups is given above. In some cases, it can be advantageous to carryout an esterification on a product whose amine and/or reactive groupswhich are present on the oxylimino are blocked before removing theprotective group of the amine and the reactive group which are presenton the oxyimino.

The products of formula I comprise several asymmetrical carbons. In thecephem nucleus which comprises two asymmetrical carbons, the two carbonsare in R configuration. Furthermore, the group present on the oxyiminofunction also has an asymmetrical carbon: ##STR17## which can be in R orS form or in the form of an R, S mixture. The separation of the twodiastereoisomers can be carried out by ways known to one skilled in theart, for example, by chromatography.

The novel antibiotic compositions of the invention are comprised of anantibiotically effective amount of at least one compound of formula Iand its non-toxic, pharmaceutically acceptable acid addition salts andan inert pharmaceutical carrier. The compositions may be in the form oftablets, dragees, capsules, granules, suppositories, ointments, creams,gels and injectable preparations.

Examples of suitable excipients are lactose, starch, magnesium stearate,cocoa butter, aqueous or non-aqueous vehicles, fatty substances ofanimal or vegetable origin, paraffin derivatives, glycols, variouswetting, dispersing or emulsifying agents, preservatives.

These compositions can preferably be in the form of a powder to bedissolved extemporaneously in an appropriate vehicle, for example,apyrogenic sterile water.

The compositions are effective against gram (+) bacteria such asstaphylococcus, streptococcus and notably on penicillin-resistantstaphylococcus. Their effectiveness against gram (-) bacteria notably oncoliform bacteria, klebsiella, salmonella, proteus and pseudomonas, isparticularly remarkable.

These compositions are useful in the treatment of affections caused bysensitive germs and notably in that of staphylococcis such asstaphylococcus septicemia, malignant staphylococcis of the face or skin,pyodermitis, septic or suppurating wounds, anthrax, phlegmons,erysipelas, acute primitive or post-influenza staphylococcis,bronchopneumonia, lung suppurations as well as in the treatment ofcolibacillosis and associated infections, in infections due to proteus,klebsiella and salmonella and in other affections caused by gram (-)bacteria. The compositions may also be used on disinfectants forsurgical instruments.

The novel method of the invention for treating bacterial infections inwarm-blooded animals, including humans, comprises administering towarm-blooded animals an antibiotically effective amount of at least onecompound of formula I and its non-toxic, pharmaceutically acceptableacid addition salts. The compounds may be administered buccally,rectally, parenterally preferably intramuscularly or topically to theskin or mucous membranes. The usual daily dose is 3.33 to 53.33 mg/kgdepending on the condition treated, the compound used and the method ofadministration. For example, the compound of Example 1 may beadministered at a dose of 0.250 to 4 g per day orally or 0.500 to 1 gthree times a day intra-muscularly.

The novel intermediate products of the invention are the compounds offormula IV and formula V in which R_(a) is a protective group of theamino, formulae IV and V being as defined above.

The products of formula II are known from the literature i.e. EuropeanPatent Applications No. 0,238,061 or No. 0,266,060 or can be prepared byknown methods. The products of formula III are also known from theliterature, i.e. British Patent Application No. 2,134,522 or GermanPatent No. DE 3,512,225.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1[6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[(2-amino-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno[2,3-b]-pyridiniumtrifluoroacetate tetrafluoroborate Step A[6R-[3(E),6α,7β(Z)]]-dibenzyl-7-[[[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-(tribenzyl)-amino]-4-thiazolyl]-acetamido]-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylate

0.372 ml of diisopropylcarbodiimide in 1ml of methylene chloride wereadded to a mixture of 1.876 g of[[[3,4-bis-(2-methoxy-ethoxy)-methoxy]-phenyl]-(diphenyl-methoxy-carbonyl)-methoxy]imino]-[2-(triphenyl-methylamino)-4-thiazolyl]acetic acid syn isomer [described in the European Patent EP No.238,061], 0.955 g ofdibenzyl-7-amino-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylate[described in the German Patent No. DE 3,512,225] and 200 ml of driedmethylene chloride. The mixture was stirred for 45 minutes and then thesolvent was evaporated off under reduced pressure. The residue waschromatographed on silica (eluant: methylene chloride 87.5--ethylacetate 12.5) to obtain 2.1 g of a yellow product with a Rf=0.42 thinlayer chromatography, eluant: methylene chloride--ethyl acetate (8-2).

    ______________________________________                                        Infrared Spectrum:                                                            CNH             3402 cm.sup.-1                                                 ##STR18##      1792 cm.sup.-1 beta lactam 1731 cm.sup.-1 ester 1683                          cm.sup.-1 secondary amide                                     CC              1594 cm.sup.-1                                                +               1584 cm.sup.-1                                                Aromatic        1525 cm.sup.-1                                                +               1517 cm.sup.-1                                                Secondary amide 1396 cm.sup.-1                                                Ultraviolet Spectrum:                                                         1) In EtOH + 1 cm.sup.-3 CHCl.sub.2                                           infl      217         nm      epsilon = 74,300                                infl      238         nm      epsilon = 35,500                                infl      271         nm      epsilon = 20,800                                infl      296         nm      epsilon = 16,400                                2) In EtOH + HCl 0.1 N                                                        infl      217         nm      epsilon = 76,400                                infl      239         nm      epsilon = 28,800                                max       283         nm      epsilon = 26,200                                infl      271, 291 and 305                                                                          nm                                                      ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-2-[(diphenyl-methoxy-2-oxoethoxy]-imino]-[2-(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumtetrafluoroborate

A mixture of 55.9 mg of silver tetrafluoroborate, 38.8 mg ofthieno-[2,3-b]-pyridine and 5 ml of methylene chloride was treated withultrasoics and then 136 mg of the product of Step A slightly diluent inmethylene chloride was added. The mixture was stirred for 75 minutes andafter filtering and evaporating, the residue was taken up in ether. Thesolid was washed 3times with 3 ml of ether to obtain 207 mg of productwhich was purified by chromatography on silica (eluant: methylenechloride--methanol). The fractions were evaporated to obtain 62 mg ofthe desired product with a Rf=0.28 thin layer chromatography (eluant:methylene chloride--methanol (9:1).

    ______________________________________                                        Ultraviolet Spectrum:                                                         1) In EtOH                                                                    max           238 nm      epsilon = 368                                       infl          287 nm      epsilon = 168                                       max           300 nm      epsilon = 184                                       2) In EtOH, HCl 0.1 N                                                         infl          236 nm      epsilon = 333                                       max           293 nm      epsilon = 209                                       ______________________________________                                    

Step C [6R-[3(E),6α,7β(Z)]]-7-[3-[7-[(2-amino-4-thiazolyl)-[[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumtrifluoroacetate tetrafluoroborate

The following two solutions were mixed together at 0° C:

a) 0.180 g of the product of Step B, 4,3 ml of methylene chloride and0.86 ml of anisole,

b) 8.6 ml of trifluoroacetic acid and 4,3 ml of methylene chloride,

and the mixture was stirred for one hour at 0° C. After evaporating, theproduct obtained was taken up in ether and solidified. After filteringand washing with ether, 100.6 mg of product were obtained which wasplaced in 3.3 ml of a trifluoroacetic acid solution with 10% of anisole.The mixture was stirred for one hour at 0° C., followed by evaporatingthen precipitating the product in ether. After filtering and rinsing,87.9 mg of the expected product were obtained.

EXAMPLE 2[6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[2-amino-4-thiazolyl)-1-[3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumin the form of an internal salt

A mixture of 89.4 mg of the product of Example 1, 2.84 ml ofacetonitrile and 2.84 ml of a 0.1N solution of trietylamine carbonatewas eluted on an RF 18 silica column with a CH₃ CN--H₂ O (50-50)mixture. The useful fractions were lyophilized to obtain 50.8 mg of theexpected product.

    ______________________________________                                        Infrared Spectrum (Nujol):                                                    Beta lactam           1770 cm.sup.-1                                          Other C = 0's         1675 cm.sup.-1                                                                approx. 1598 cm.sup.-1                                  Ultraviolet Spectrum in EtOH, HC 0.1 N                                        max          240 nm      epsilon = 28,600                                     max          290 nm      epsilon = 24,000                                     ______________________________________                                    

EXAMPLE 3 6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thiazolo-[4,5-c]-pyridinium-trifluoroacetate iodide Step A[6R-[3(E),6α,7β(Z)]]-diphenylmethyl-7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-3-(3-iodo-1-propenyl)-8-oxo-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylate

A mixture of 650 mg of the product of Step A of Example 1, 19.1 ml ofacetone and 216.3 mg of sodium iodide was stirred for 2 hours at ambienttemperature and the solvent was evaporated off. Then, the residue wastaken up in 26.5 ml of ethyl acetate and the solution was washed 3 timeswith 15 ml of sodium thiosulfate, then twice with 15 ml of water. Afterdrying on magnesium sulfate, filtering, rinsing and evaporating, theresidue was taken up in a methylene chloride--ethyl acetate (7-3)mixture. 5.3 g of silica were added and the mixture was stirred for 5minutes followed by filtering and rinsing to obtain 445 mg of theexpected product after evaporation (Rf=0.54 on thin layerchromatography, eluant: methylene chloride--ethyl acetate (7-3)).##STR19##

Step B[6R-[3(E),6α,7η(Z)]]-5-[3-[7-[[1-[3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl]-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3-yl]-2propenyl]-thiazolo-[4,5-c]-pyridiniumiodide.

A mixture of 445.2 mg of the product of Step A in the smallest possiblequantity of dimethylsulfoxide and 48.2 mg of thiazolo-[ 4,5-c]-pyridinewas stirred for 5 hours and then the solvent was eliminated underreduced pressure. The viscous residue was washed 3 times with 7 ml ofether to obtain 374.6 mg of a solid which was purified on silica(eluant: methylene chloride--methanol (92-8)) to obtain 24 mg of producthaving the Z isomer, 21.2 mg of an E+Z mixture and 154.3 mg of producthaving the E isomer (Rf=0.18 on thin layer chromatography, eluant:methylene chloride--methanol (9-1)). ##STR20##

Step C[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino4-thiazolyl)-[1-(3,4-dihydroxy-phenyl-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2en-3-yl]-2-propenyl]-thiazolo-[4,5-c]-pyridiniumtrifluoroacetate iodide

A mixture of the two following solutions was stirred for one hour at 0°C.:

a) 238.6 mg of the product of Step B, 5.7 ml of methylene chloride and1.14 ml of anisole and

b) 11.4 ml of trifluoroacetic acid in 5.7 ml of methylene chloride.

The solvents were evaporated and then the product was precipitated inether. After filtering and washing, 0.124 g of the expected product wereobtained which was mixed with 4.14 ml of trifluoroacetic acid and 0.46ml of anisole. The mixture was stirred for 40 minutes at a temperatureof 0° C. After evaporating, the product was precipitated in ether. Afterfiltering, rinsing with ether and drying, 95.8 mg of the expectedproduct were obtained.

EXAMPLE 4[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[(2-amino-4thiazolyl)-[[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3yl]-2-propenyl]-thiazolo-[4,5c]-pyridiniumin the form of an internal salt

A solution of 95 mg of the product of Example 3, 3.6 ml of acetonitrileand 3.8 ml of triethylamine carbonate was passed through an RP18 silicacolumn. The column was eluted with a mixture of acetonitrile-water(50-50) and the useful fractions were lyophilized to obtain 63.8 mg ofthe expected product.

    ______________________________________                                        Ultraviolet Spectrum (in EtOH, HCl 0.1 N)                                     max       225         nm      epsilon = 38,500                                max       286         nm      epsilon = 23,500                                infl      274, 300 and 356                                                                          nm                                                      Infrared Spectrum (Nujol)                                                      ##STR21##         1770 cm.sup.-1 Beta lactam 1676 cm.sup.-1 complex          Aromatic region    1626 cm.sup.-1                                             COO.sup.⊖  1596 cm.sup.-1                                             Secondary amide    1536 cm.sup.-1                                             ______________________________________                                    

EXAMPLE 5[6R-[3(E),6α,7β(Z)]]-4-[3-[[[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-thieno-[3,2-b]-pyridiniumtrifluoroacetate tetrafluoroborate Step A[6R-[3(E),6α,7β(Z)]]-4-[3-[7-[[3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-[(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-(triphenylmethyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-thieno-[3,2-b]-pyridiniumtetrafluoroborate

Using the procedure of Step B of Example 1, 1.2 g of the product of StepA of Example 1, 346 mg of silvere fluoroborate in 44 ml of methylenechloride and 0.24 ml of thieno-[3,2-b]-pyridine were reacted to obtainafter chromatography on silica (eluant: methylene chloride--methanol92-8 then 96-4) 337 mg of the expected product:

    ______________________________________                                        NMR Spectrum (CDCl.sub.3 300 Hz)                                              ______________________________________                                         ##STR22##       6.23 (dm, J=16) delta E                                       ##STR23##       5.44 (m)                                                     the CH's of the thienyl                                                                        7.67 (d, resolved) 8.25 (d,                                                   resolved)                                                    the CH's of the pyridine                                                                       7.76 (m), 8.74 (d, resolved), 8.93                                            (d, resolved)                                                ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-4-[3-[[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)propenyl]-thieno-[3,2-b]-pyridinium trifluoroacetate tetrafluoroborate

Using the procedure of Step C of Example 1, 316.1 mg of the product ofStep A, 1.51 ml of anisole in 7.5 ml of methylene chloride and 13.7 mlof trifluoroacetic acid in 7.5 ml of methylene chloride were reacted toobtain 183 mg of product to which another 6.3 ml of trifluoroacetic acidwith 10% anisole were added. The mixture was stirred for 1 hour at 0° C.and the solvent was evaporated off. The residue was taken up in etherand the precipitate was filtered, washed with ether and dried underreduced pressure to obtain 124.1 mg of the expected product.

    ______________________________________                                        NMR (DMSO)                                                                    ______________________________________                                         ##STR24##         5.33 (s)                                                   CHS                5.15 (d)                                                   SCH.sub.2          3.49 (m) partially masked                                   ##STR25##         6.33 (dt, J=5 and 8) delta E                                ##STR26##                                                                    H.sub.7            5.72 (m)                                                   N.sup.⊕ CH.sub.2                                                          phenyl                                                                        H.sub.5 thiazole   6.57 to 7.07                                               mobile H                                                                      H.sub.6 ', H.sub.3 ', H.sub.2 ', H.sub.7 ', H.sub.5 ', of                                        8.04 to 9.36                                               pyridine                                                                      ______________________________________                                    

EXAMPLE 6[6R-[3(E),6α,7β(Z)]]-4-[3-[[[(2-amino-4thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-thieno-[3,2-b]-pyridiniumtrifluoroacetate tetrafluoroborate Step A[6R-[3(E),6α,7β(Z)[[-diphenylmethyl-7-[[1-[3,4-bis[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-3-(3-iodo-1-propenyl)-8-oxo-5-thia1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

Using the procedure of Step A of Example 3, 3 g of the chlorinatedproduct of Step A of Example 1 in 100 ml of acetone and 1.0 g of sodiumiodide were reacted to obtain 3.3 g of iodinated derivative identical tothat obtained in Example 3 which was used as in the following step.

Step B[6R-[3(E),6α,7β(Z)]]-4-[3-[7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[3,2-b]-pyridiniumiodide

Using he procedure of Step B of Example 3, 3.3 g of the iodinatedderivative of Step A, 1.5 ml of thieno-[2,3-b]-pyridine and replacingthe dimethylsulfoxide with methylene chloride were reacted to obtain1.08 g of the expected product.

    ______________________________________                                        NMR Spectrum:                                                                 ______________________________________                                         ##STR27##         5.69 to 5.84 (m) 3H (+H.sub.7)                              ##STR28##         6.33 (dt), 6.46 (dt)                                       H of thienopyridine                                                                              7.83 to 9.72                                               ______________________________________                                    

Step C[6R-[3(E),6α,7β(Z)]]-4-[3-[[(2-amino-4-thiazolyl)-[[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-(E)-propenyl]-thieno-[3,2-b]-pyridiniumtrifluoroacetate tetrafluoroacetate

The following two solutions were mixed together at 0° C. and stirred forone hour: a) 55 ml of trifluoroacetic acid, 5.5 ml of anisole and 25 mlof methylene chloride and b) 1.19 g of the product of Step B in 20 ml ofmethylene chloride and the synthesis was continued as in Step C ofExample 3 to obtain 0.62 g of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 Hz)                                                    ______________________________________                                         ##STR29##         5.33 (s)                                                   CHS                5.15 (d, resolved)                                         SCH.sub.2          3.49 (m) partially masked                                   ##STR30##         6.33 (dt, J=16 and 8) delta E                               ##STR31##         5.72 (m)                                                   and                                                                           CHCHCH.sub.2                                                                  phenyl                                                                        H.sub.5 thiazole   6.57 to 7.01                                               mobile H                                                                      H.sub.6 ', H.sub.3 ', H.sub.2 ', H.sub.7 ', H.sub.5 ', of                                        8.04 to 9.36                                               pyridine                                                                      ______________________________________                                    

EXAMPLE 7[6R-[3(E),6α,7β-(Z)[]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-pyridiniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β-(Z)[]-1-[3-[7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxo-ethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-pyridiniumiodide

Using the procedure of Step B of Example 6, 1.47 g of the ioinatedderivative of Step A of Example 3 and 480 micro liters of pyridine werereacted to obtain 0.640 g of the expected product.

    ______________________________________                                        NMR (CDCl.sub.3 400 MHz):                                                     ______________________________________                                         ##STR32##        5.15 to 5.50                                                 ##STR33##        6.5 (dt, resolved) delta E                                  H.sub.2 and H.sub.6 of pyridine                                                                 9.10 (m)                                                    H.sub.3 and H.sub.5 of pyridine                                                                 7.87 (m)                                                    H.sub.4 of pyridine                                                                             8.27 (t, resolved)                                          ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-pyridiniumtrifluoroacetate hydroiodide

Using the procedure of Step C of Example 6, 0.638 g of the derivative ofStep A were reacted to obtain 0.314 g of the expected product.

    ______________________________________                                        NMR Spectrum:                                                                 ______________________________________                                         ##STR34##            5.32 (s)                                                H.sub.6               5.14 (d) and 5.17 (d)                                   H.sub.7               5.77 (m)                                                H.sub.5 thiazole      6.87 (sl)                                                ##STR35##            9.55 (d) and 9.62 (d)                                   phenyl                6.65 to 6.80                                             ##STR36##            7.01 (d, resolved)                                       ##STR37##            6.30 (dt) delta E                                       CHCHCH.sub.2          aprox. 5.41                                             H in position 2 and 6 of pyridine                                                                   9.05 (d)                                                H in position 3 and 5 of pyridine approx.                                                           813 (d)                                                 H in position 4 of pyridine                                                                         8.64 (t)                                                ______________________________________                                    

EXAMPLE 8[6R-[3(E),6α,7β(Z)]]-6-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-c]-pyridiniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-6-[3-[7-[[1-(3,4-bis-[2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxo-ethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-c]-pyridinium-iodide

Using the procedure of Step B of Example 6, 2.08 g of the iodinatedderivative of Step A of Example 3 and 1 g of thieno[ 2,3-c]-pyridinewere reacted to obtain 0.98 g of the expected product.

    ______________________________________                                        NMR Spectrum:        1) In EtOH:                                              ______________________________________                                        Infl.   220 nm           epsilon = 87,500                                     max.    239 nm           epsilon = 57,000                                     Infl.   274 nm           epsilon = 25,500                                     max.    306 nm           epsilon = 27,000                                     1) In EtOH/HCl 0.1 N:                                                         Infl.   220 nm           epsilon = 87,800                                     Infl.   236 nm           epsilon = 53,600                                     max.    284 nm           epsilon = 32,600                                     max.    293 nm           epsilon = 32,500                                     Infl.   320 nm           epsilon = 24,000                                     ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-6-[3-[7-[[2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-c]-pyridiniumtrifluoroacetate hydroiodide

Using the procedure of Step C of Example 6, 0.966 g of the iodinatedderivative of Step A were reacted to obtain 0.487 g of the expectedproduct.

    ______________________________________                                        NMR Spectrum:                                                                 ______________________________________                                         ##STR38##           5.32 (s)                                                 H.sub.7              5.78 (m)                                                 H.sub.5 thiazole     6.86 (sl)                                                phenyl               6.65 to 6.80                                             H.sub.6, H.sub.7 thienopyridine                                                                    7.94 (d), 8.81 (d)                                       H.sub.4, H.sub.5 thienopyridine                                                                    8.53 (d), 8.78 (d)                                       H.sub.2 thienopyridine                                                                             9.91 (s)                                                  ##STR39##           7.08 (dl, J=15.5)                                         ##STR40##           6.35 (m) delta E                                          ##STR41##           5.47 (d)                                                 ______________________________________                                    

EXAMPLE 9[6R-[3(E),6α,7β(Z)]]-1[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-6,7-dihydro-5H-pyrindiniumtrifluoroacetate iodide Step A[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-6,7-dihydro-5H-pyrindiniumiodide

Using the procedure of Step B of Example 6, 1.33 g of the iodinatedderivative of Step A of Example 3 and 0.585 ml of cyclopentyl pyridinewere reacted to obtain 1.07 g of the expected product.

Step B[6R-[3(E),6α,7β(Z)]]1-[3-[7-[[2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-6,7-dihydro-5H-pyrindiniumtrifluoroacetate iodide

Using the procedure of Step C of Example 6, 1.053 g of the product ofStep A were reacted to obtain the expected product.

    ______________________________________                                        NMR SPECTRUM                                                                  (DMSO 300 MHz)                                                                ______________________________________                                        CH.sub.2 N.sup.+                                                                             5.32 (m) 3H                                                    OCH                                                                           Aromatic H's                                                                  H.sub.5 thiazole                                                                             6.70 to 6.90                                                    ##STR42##                                                                    H.sub.6        5.16 (d, resolved)                                             H.sub.7        5.77 (m, d, resolved after exchange)                           SCH.sub.2      3.4 to 3.8 (m)                                                 CHCHCH.sub.2   6.23 (d, t) delta E                                            H of cyclopentyl                                                                             2.23-3.15-3.8                                                  H of pyridine  7.2 (m), 8.42 (d), 8.76 (d)                                    Mobile H       9.01 to 9.62                                                    ##STR43##     5.47 (d)                                                       ______________________________________                                    

EXAMPLE 10[6R-[3(E),6α,7β(Z)]]-2-amino-5-[3-[7-[(2-amino-4-thiazolyl)-[[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-yl]-2-propenyl]-thiazolo-[4,5-c]-pyridiniumtrifluoroacetate iodide Step A[6R-[3(E),6α,7β(Z)]]-2-amino-5-[3-[7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-2[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(diphenylmethoxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thiazolo-[4,5-]-pyridiniumiodide

Using the procedure of Step B of Example 6, the iodinated derivative ofStep A of Example 3, prepared from 272 mg of the chlorinated derivativeand 90 mg of sodium iodide and 30 mg of amino thiazolo pyridine werereacted to obtain 42 mg of expected product.

Step B[6R-[3(E),6α,7β(Z)]]-2-amino-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thiazolo-[4,5,-c]-pyridiniumtrifluoroacetate iodide.

Using the procedure of Step C of Example 3, 130 mg of the product ofStep A were reacted to obtain 11.5 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 MHz)                                                   ______________________________________                                        H.sub.5 thiazole                                                              ethylenic             6.64 to 7.41                                            aromatics                                                                     H.sub.6                                                                       N.sup.⊕ CH.sub.2 CH                                                                             5.05 to 5.35                                            OCH                                                                           H.sub.7               5.67 (m), 5.76 (m)                                       ##STR44##            6.29                                                    H.sub.6, H.sub.7 of thiazolo pyridine                                                               8.42 (d), 8.49 (d)                                      H.sub.2 of thiazolo pyridine                                                                        8.99 (sl)                                                                     8.67                                                    mobile protons        9 (m)                                                                         9.54 (m)                                                                      10.15                                                   ______________________________________                                    

EXAMPLE 11[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[3,2-c]-pyridiniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-p-methoxybenzyl-7-[[1-[3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl-2-carboxylate

A suspension of 3.75 g of[[(3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-aceticacid syn isomer [described in European Patent No. 238,061] and 1.81 g ofmethoxybenzyl-7-amino-3-(3-chloropropenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate[prepared in European Patent No. 0,333,154] in methylene chloride wascooled to 0° C. and 0.920 g of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were added. The solution was stirred at 0° C.for 30 minutes and the organic phase was washed with an aqueous solutionof sodium chloride and dried. The solvents were eliminated and afterchromatographing the residue on silica (eluant: methylenechloride--ether 85-15) and solidification in isopropyl ether, 4.546 g ofthe expected product was obtained.

    ______________________________________                                        NMR Spectrum (CDCl.sub.3 400 MHz)                                             ______________________________________                                         ##STR45##              5.10 to 5.32                                           ##STR46##              3.80                                                  ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-p-methoxybenzyl-7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-3-(3-iodo-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl-2-carboxylate

A mixture of the product of Step A, 10 ml of acetone and 341 mg ofsodium iodide and approximately 10 mg of iodine was stirred for one hourat ambient temperature and the solvent was evaporated. The residue wastaken up in 80 ml of methylene chloride and the organic phase was washedwith an aqueous solution of sodium thiosulfate, then with water. Afterdrying, the solvents were eliminated and the residue was chromatographedon silica (eluant: methylene chloride--ethyl acetate 8-2) to obtain 853mg of the expected product.

    ______________________________________                                        NMR Spectrum (CDCl.sub.3                                                      300 MHz)                                                                      ______________________________________                                         ##STR47##                                                                    aromatics        6.9 to 7.35                                                  CHC                                                                            ##STR48##       6.13 (d, t J=15 and 8) delta E                                ##STR49##       4.0 (d)                                                      ______________________________________                                    

Step C[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[1-[3,4-bis-[2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(paramethoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[3,2-c]-pyridiniumiodide

2.48 g of the iodinated derivative of Step B were dissolved in 10 ml ofmethylene chloride and 1.2 g of thieno-[3,2-c]-pyridine in solution in 2ml of methylene chloride was added. Trituration took place for 1 hour atambient temperature and 70 ml of ether were added. The precipitate wasfiltered, washed with ether and chromatographed on silica (eluant:methylene chloride--methanol 95-5) to obtain 1.117 g of the expectedproduct.

Step D[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[3,2-c]-pyridiniumtrifluoroacetate hydroiodide

Using the procedure of Step C of Example 6, 1.117 g of the product ofStep C were reacted to obtain 0.618 g of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 300 MHz)                                                   ______________________________________                                         ##STR50##          5.33 (s)                                                  H.sub.6             5.18                                                      H.sub.7             5.79 (m)                                                   ##STR51##          9.56 (d), 9.64 (d)                                         ##STR52##          7.07 (d, J=15.5) delta E                                   ##STR53##          6.36 (m)                                                  H of thienopyridine 8 to 9.71                                                 aromatics and H.sub.5 thiazole                                                                    6.70 to 6.78; 6.85 (s,1)                                  mobile H's          12.56                                                     ______________________________________                                    

EXAMPLE 12[6R-[3(E),6α,7β(Z)]]-2-[3-[7-[(2-amino-4-thiazolyl)-[[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl)-2-propenyl]-isoquinoliniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-2-[3-[7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyl)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-isoquinoliniumiodide

Using the procedure of Step B of Example 6, 2.48 g of iodinatedderivative of Step B of Example 11 and 1.04 ml of isoquinoline werereacted to obtain 1.26 g of the expected product.

Step B[6R-[3(E),6α,7β(Z)]]-2-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-actamido]-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-isoquinoliniumtrifluoroacetate hydroiodide

Using the procedure of Step C of Example 6, 1.26 g of the product ofStep A were reacted to obtain 0.673 g of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 300 MHz):                                                  ______________________________________                                         ##STR54##         5.32 (s)                                                   H.sub.6            5.17 (m)                                                   H.sub.7            5.77 (m)                                                    ##STR55##         3.07                                                        ##STR56##         9.54 (d), 9.62 (d)                                          ##STR57##         7.10 delta E                                                ##STR58##         6.37 (m) delta E                                            ##STR59##         5.53 (d)                                                   H of isoquinoline  8.9 to 10.06                                               aromatics and H.sub.5 thiazole                                                                   6.45 to 6.37 (3H); 6.85 (s) 1H                             mobile H's         7.30 (2H); 9 (2H)                                          ______________________________________                                    

EXAMPLE 13[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-2-methyl-1H-imidazo-[4,5-c]-pyridiniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyl)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-2-methyl-1H-imidazo-[4,5-c]-pyridiniumiodide

Using the procedure of Step B of Example 6, 1.92 g of the iodinatedderivative of Step B of Example 11 and 0.29 g of 2-methyl-1H-imidazo-[4,5-c]-pyridine were reacted to obtain 1.055 g of theexpected product.

Step B [6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-2-methyl-1H-imidazo-[4,5-c]-pyridiniumtrifluoroacetate hydroiodide

Using the procedure of Step C of Example 6, 1.043 g of the product ofStep A were reacted to obtain 0.608 g of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 300 MHz):                                                  ______________________________________                                         ##STR60##      5.32 (s)                                                      H.sub.6         5.15 (d, resolved)                                            H.sub.7         5.77 (m, d, resolved after exchange                            ##STR61##      3.76 (d), 3.61 (masked)                                        ##STR62##      9.55 (d), 9.63 (d)                                             ##STR63##      6.95 (dl)                                                      ##STR64##      6.35 (dt) delta E                                              ##STR65##      5.42 (m)                                                      CH.sub.3 of imidazopyridine                                                                   2.70 (s)                                                      H of pyridine   8.16 to 9.47                                                  aromatics and H.sub.5 thiazole                                                                6.65 to 6.80 (m) 3H; 6.86 (s) 1H                              mobile H's      7.34 (2H); 9.05 (m)                                           ______________________________________                                    

EXAMPLE 14[6R-[3(E),6α,7β(Z)]]-3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-N,N,N-trimethyl-2-propen-1-aminium-trifluoroacetate iodide Step A[6R-[3(E),6α,7β(Z)]]-3-[7-[[1-[3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxo-ethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-N,N,N-trimethyl-2-propen-1-aminium iodide

365 mg of the iodinated derivative of Step B of Example 11, 0.7 ml oftetrahydrofuran and 220 micro liters of a solution of trimethylamine inether (2.37 M/l) were stirred for 40 minutes at ambient temperature. 20ml of ether were added and the precipitate was separated andchromatographed on silica (eluant: methylene chloride--methanol 92-8).The residue was taken up in either and after elimination of the solvent,276 mg of the expected product were obtained.

    ______________________________________                                        Infra-Red Spectrum:                                                           CNH                3404 cm.sup.-1 + associated                                O                  1791 cm.sup.-1 (beta lactam)                                                  1728 cm.sup.-1 esters                                                         1685 cm.sup.-1 amide                                       Conjugated system +                                                                              1632 cm.sup.-1 (shoulder)                                  amide II +         1613 cm.sup.-1                                             aromatic           1596 cm.sup.-1                                                                1586 cm.sup.-1                                                                1525 cm.sup.-1                                                                1517 cm.sup.-1                                                                1496 cm.sup.-1                                             Ultra-violet Spectrum                                                         1) In ethanol + 1 ml CH.sub.2 Cl.sub.2                                        infla      219 nm      epsilon = 74,000                                       max.       281 nm      epsilon = 23,600                                       infl.      295 nm      epsilon = 22,100                                       infl.      265, 276 nm                                                        2) In ethanol HC1 0.1 n                                                       infl.      219 nm      epsilon = 75,000                                       max.       283 nm      epsilon = 30,000                                       ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-N,N,N-trimethyl-2-propen-1-aminiumtrifluoroacetate iodide

247 mg of the product of Step A and 2.5 ml of trifluoroacetic acid with10% of anisole were stirred for 1 hour at ambient temperature and 25 mlof isopropyl ether were added. The mixture was stirred for 10 minutesand the precipitate was isolated and dried under reduced pressure at 20°C. for 24 hours to obtain 128 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 300 MHz):                                                  ______________________________________                                        NOCHCO.sub.2 H        5.33 (s)                                                H.sub.6               5.16 (d)                                                H.sub.7               5.76 (d)                                                 ##STR66##            9.08 (d)                                                 ##STR67##            6.07 (m) delta E                                         ##STR68##            7.04 (d)                                                 ##STR69##            4.05 (d)                                                .sup.+ N(CH.sub.3).sub.3                                                                            2.99 (s), 3,03 (s)                                      aromatics and H.sub.5 thiazole                                                                      6.70 to 6.9                                             ______________________________________                                    

EXAMPLE 15[6R-[3(E),6α,7β(Z)]]-[3-[7-[[(2-amino-4-thiazolyl)[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]-oct-2-en-3-yl]-N-(cyanomethyl)-N,N-dimethyl-2-propen-1-aminium]-trifluoroacetateiodide Step A [6R-[3(E),6α,7β(Z)]]-[3-[7-[[1-(3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-en-3-yl]-N-(cyanomethyl)-N,N-dimethyl-2-propen-1-aminium]-iodide

Using the procedure of Step A of Example 14, 250 mg of the iodinatedderivative of Example 14 and 250 ml of a solution of dimethylaminoacetonitrile in tetrahydrofuran (1-9) were reacted to obtain 172 mg ofthe expected product.

    ______________________________________                                        NMR Spectrum (CDCl.sub.3 400 MHz):                                            ______________________________________                                         ##STR70##          6.05 (d, t) delta E                                        ##STR71##          5.05 to 5.35                                               ##STR72##                                                                    .sup.+ NCH.sub.2 CN 4.35 to 4.5                                               the CH.sub.3 's     3.07 to 3.9                                               ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-N-(cyanomethyl)-N,N-dimethyl-2-propen-1-aminium]-trifluoroacetate iodide

Using the procedure of Step B of Example 14, 172 mg of the product ofStep A were reacted to obtain 72 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 300 MHz):                                                  ______________________________________                                         ##STR73##          5.33 (s)                                                  H.sub.6             5.20 (d)                                                  H.sub.7             5.82 (m)                                                   ##STR74##          9.54 (d)                                                   ##STR75##           7.1 (d)                                                   ##STR76##          6.13 (m)                                                   ##STR77##          4.24 (d)                                                  .sup.⊕ N(CH.sub.3).sub.2                                                                      3.19 (s)                                                   ##STR78##           4.8 (s)                                                  aromatics and H.sub.5 thiazole                                                                    6.65 to 6.80 and 6.87                                     mobile H's          7.79; 9.07                                                ______________________________________                                    

EXAMPLE 16[6R-[3(E),6α,7β(Z)]]-N-(2-amino-2-oxoethyl)-[3-[7-[[(2-amino)-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxo-ethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-N,N-dimethyl-2-propen-1-aminium]-trifluoroacetateiodide Step A[6R-[3(E),6α,7β(Z)]]-N-(2-amino-2-oxoethyl)-[3-[7-[[1-(3,4-bis[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-yl]-N,N,-dimethyl-2-propen-1-aminium]iodide

350 mg of the iodinated derivative of Step B of Example 11 were mixedover one hour at 20° C. with 1.6 ml of acetonitrile and 27 mg ofdimethylaminoacetamide. The solvents were eliminated under reducedpressure and the residue was chromatographed to silica (eluant:methylate chloride--methanol 97-3then 92-8) to obtain 300 mg of theexpected product.

    ______________________________________                                        NMR Spectrum (CDCl.sub.3 300 MHz):                                            ______________________________________                                         ##STR79##            6.10 delta E                                             ##STR80##            4.56                                                     ##STR81##                                                                    aromatic H's          6.85 to 7.37                                            NH.sub.2                                                                      the CH.sub.3 's       3.24 to 3.35                                             ##STR82##            4.23 (m)                                                ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]-N-(2-amino-2-oxoethyl)-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-en-3-yl]-N,N-dimethyl-2-propen-1aminium]-trifluoroacetateiodide

Using the procedure of Step B of Example 14, 285 mg of the product ofStep A were reacted to obtain 152 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 300 MHz):                                                  ______________________________________                                         ##STR83##        5.34 (s)                                                    H.sub.6           5.19 (d)                                                    H.sub.7           5.85 (m)                                                    the NH's          9.55 (d); 9.62 (d)                                           ##STR84##        7.03 (d, J=13.5) delta E                                     ##STR85##        6.13 (m)                                                     ##STR86##        4.27 (d)                                                    .sup.⊕ N(CH.sub.3).sub.2                                                                    3.19 (s)                                                    .sup.⊕ NCH.sub.2                                                                            4.01 (s)                                                    aromatics and H.sub.5 thiazole                                                                  6.72 to 6.8                                                 mobile H's                                                                    ______________________________________                                    

EXAMPLE 17[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-1-methyl-pyrrolidiniumtrifluoroacetate iodide Step A[6R-[3(E),6α,7β(Z)]]-[3-[7-[[1-(3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-[(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-en-3-yl]-2-propenyl]-1-methyl-pyrrolidiniumiodide

357 mg of the iodinated derivative of Step B of Example 11 weredissolved at 20° C. in 7 ml of ether and 1.3 ml of methylene chlorideand 130 microliters of methyl-pyrrolidine and 5 ml of ether were added.The mixture was stirred for 10 minutes and the precipitate was isolatedand dried at 20° C. under reduced pressure to obtain 300 mg of theexpected product.

Step B[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-1-methylpyrrolidinium trifluoroacetate iodide

Using the procedure of Step B of Example 14, 290 mg of the product ofStep A were reacted to obtain 150 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 300 MHz):                                                  ______________________________________                                         ##STR87##         5.34 (s)                                                   H.sub.6            5.18 (d)                                                   H.sub.7            5.79 (m)                                                    ##STR88##         9.52 (d); 9.61 (d)                                          ##STR89##         7.05 (d, J=15) delta E                                      ##STR90##         6.17 (m) delta E                                            ##STR91##         4.11 (d)                                                   .sup.⊕ NCH.sub.3                                                                             2.99 (s)                                                   pyrrolidine        2.10 (sl), 3.45 (sl)                                       aromatics and H.sub.5 thiazole                                                                   6.65 to 6.85                                               mobile H's         9.10                                                       ______________________________________                                    

EXAMPLE 18 [6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[(2-amino-4-thiazolyl)-[(R)1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxo-ethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-p-methoxybenzyl-7-[[(R)-1-(3,4-dihydroxy)-phenyl]-2-(diphenylmethoxy)-2-oxoethoxy]-imino[]2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl-2-carboxylate

1.1 g of [[(R) (3,4-dihydroxyphenyl)-(diphenylmethoxy-carbonyl)-methoxy]-imino]-[2-(tribenzyl)-4-thiazolyl]-aceticacid syn isomer [prepared for isomer S is European Patent No. 0,266,060and 0,280,521 or in German Patent No. DE 3,742,457 A1] dissolved in11.36 ml of methylene chloride were cooled to -5° C. and 403.4 mg ofdicylocarbodiimide were added. The mixture was stirred for 40 minutesand 668 mg ofp-methoxybenzyl-7-amino-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylatehydrochloride [European Patent No. 0,333,154] were added, The mixturewas stirred for 3 hours while allowing the temperature to return toambient and the solvents were eliminate. The residue was chromatographedon silica (eluant: methylene chloride--ethyl acetate 9-1) to obtain 7.12mg of the expected product.

    ______________________________________                                        NMR Spectrum (CDl.sub.3 300 MHz)                                              ______________________________________                                         ##STR92##         6.74 to 7.34                                               H.sub.5 thiazole                                                               ##STR93##                                                                     ##STR94##         6.25 (d, J=1) delta Z                                       ##STR95##         3.73 (dd)                                                                     3.92 (dd)                                                   ##STR96##         5.18 (s)                                                                      5.24                                                        ##STR97##         3.81 (s)                                                   ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-p-methoxybenzyl-7-[[(R)-1-(3,4-[(dihydroxy)-phenyl]-2-(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-3-(3-iodo-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl-2-carboxylate

A mixture of 590 mg of the product of Step A, 11.9 ml of acetone and 216mg of sodium iodide was stirred for 2 hours at ambient temperature andthe solvent was evaporated. The residue was taken up in 5 ml ofmethylene chloride and the solution was washed 3 times with 10 ml ofsodium thiosulfate, then twice with 10 ml of an aqueous solution ofsodium chloride. After drying and crystallizing from ether, 456.6 mg ofthe expected product were obtained.

    ______________________________________                                        NMR Spectrum (CDCl.sub.3                                                      400 MHz):                                                                     ______________________________________                                         ##STR98##      5.86 (s)                                                      H.sub.6         4.85 (d)                                                      H.sub.7         5.74 (dd)                                                      ##STR99##      3.24                                                           ##STR100##     8.10 (d)                                                       ##STR101##     6.00 (d, J=15.5 and 17.5) delta E                              ##STR102##     3.82 (d), 3.98 (d)                                             ##STR103##     5.24                                                          OCH.sub.3       3.80 (s)                                                      aromatics and H.sub.5 thiazole                                                                6.68 to 7.40                                                  ______________________________________                                    

Step C[6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[(R)-1-(3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumiodide

446 mg of the iodinated derivative of Step B and 0.44 ml of thienopyridine were stirred and triturated for 2 hours at ambient temperature.Ether was added and the solid was dried under reduced pressure for 24hours to obtain 442 mg of the expected product.

    ______________________________________                                        NMR Spectrum:                                                                 NOCH                 5.55                                                      ##STR104##          6.30 (m) delta E                                         NMR Spectrum:                                                                 NOCH                 5.55                                                      ##STR105##          6.30 (m) delta E                                          ##STR106##          5.63 to 5.69                                             H.sub.7                                                                       H of the thieno pyridine                                                                           7.89 to 9.21                                             ______________________________________                                    

Step D[6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[(2-amino-4-thiazolyl)-[(R)1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxo-ethoxy]-imino]-acetamido]2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumtrifluoroacetate hydroiodide

632 mg of the product of Step C in 6.32 ml of a solution oftrifluoroacetic acid with 10% anisole were stirred for one hour atambient temperature and the mixture was cooled to +5° C. 65 ml ofisopropyl ether were added, followed by stirring for 10 minutes,filtering and drying under reduced pressure at ambient temperature for16 hours to obtain 403 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 MHz):                                                  ______________________________________                                         ##STR107##         5.31 (s)                                                  H.sub.6             5.18 (d)                                                  H.sub.7             5.77 (dd)                                                  ##STR108##         3.73 (m)                                                   ##STR109##         7.15 (d, J=16) delta E                                     ##STR110##         6.30 (d,t)                                                 ##STR111##         5.68 (d)                                                  H of the thieno pyridine                                                                          7.88 to 9.23                                              aromatics, NH, H.sub.5 thiazole                                                                   6.70 to 7.35 (approx. 6H)                                 mobile H's          7.31 to 9.61                                              ______________________________________                                    

EXAMPLE 19[6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[(2-amino-4-thiazolyl)-[(S)-1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxo-ethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno[-2,3-b]-pyridiniumtrifluoroacetate iodide Step A[6R-[3(E),6α,7β(Z)]]-p-methoxybenzyl-7-[[(S)-1-(3,4-dihydroxy)-phenyl]-2-(diphenylmethoxy)-2-oxoethoxy]-imino]-2-[(tribenzyl)-amino]-4-thiazolyl-acetamido]-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl-2-carboxylate

Using the procedure of Step A of Example 18, 678 mg of [[(S)(3,4-dihydroxyphenyl)-(diphenylmethoxycarbonyl)-methoxy]-imino]-[2-(triphenyl-methylamino)-4-thiazolyl]-aceticacid syn isomer [European Patents No. 0,266,060 and 0,280,521 or in theGerman Patent DE 3,732,457 A1] and 412 mg of p-methoxybenzyl7-amino-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylatehydrochloride were reacted to obtain 590 mg of the expected product.

    ______________________________________                                        NMR Spectrum (CDCl.sub.3 400 MHz):                                            ______________________________________                                        NOCH                   5.89 (s)                                                ##STR112##            5.81 (d, t)                                                                   6.34 (d, J=12)                                         ______________________________________                                    

Step B[6R-[3(E),6α,7β(Z)]]-p-methoxybenzyl-7-[[(S)-1-(3,4-dihydroxy)-phenyl]-2-(diphenylmethoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino-4-thiazolyl]-acetamido]-3-(3-iodo-1-propenyl)-8-oxo-5-thia-1-azabicyclo-[4',2,0]-oct-2-en-3-yl-2-carboxylate

Using the procedure of Step B of Example 18, 850 mg of the product ofStep A and 335 mg of sodium iodide were reacted to obtain 595 mg of theexpected product.

    ______________________________________                                        Infra Red Spectrum (CHCl.sub.3):                                               ##STR113##                                                                                        ##STR114##                                                aromatic heterocycle amide II CC                                                                  ##STR115##                                               Ultra Violet Spectrum:                                                        1) in dioxane                                                                 infl. 224 nm     E.sub.1.sup.1 = 566                                                                      epsilon = 69,600                                  infl. 242 nm     E.sub.1.sup.1 = 345                                          infl. 275 nm     E.sub.1.sup.1 = 197                                          max. 282 nm      E.sub.1.sup.1 = 201                                                                      epsilon = 24,700                                  infl. 290 nm     E.sub.1.sup.1 = 195                                          max. 314 nm      E.sub.1.sup.1 = 218                                                                      epsilon = 26,800                                  2) in dioxane/HCl 0.1N                                                        max. 285 nm      E.sub.1.sup.1 = 266                                                                      epsilon = 32,700                                  infl. 304 nm     E.sub.1.sup.1 = 244                                                                      epsilon = 30,000                                  infl. 320 nm     E.sub.1.sup.1 = 188                                                                      epsilon = 23,100                                  ______________________________________                                    

Step C [6R-[3(E),6α,7β(Z)]]-7-[3-[7-[[(S)-1-(3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-[(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumiodide

Using the procedure of Step C of Example 18, 430 mg of the iodinatedderivative of Step B and 470 mg of thieno pyridine were reacted toobtain 438 mg of the expected product.

    ______________________________________                                        Infra Red Spectrum (CHCl.sub.3):                                              NH/OH region complex                                                          ______________________________________                                         CO                                                                                                ##STR116##                                                ##STR117##                                                                                        ##STR118##                                               ______________________________________                                    

Step D [6R-[3(E),6α,7β(Z)]]-7-[3-[7-[(2-amino-4-thiazolyl)-[(S)-1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumtrifluoroacetate iodide

Using the procedure of Step D of Example 18, 400 mg of the product ofStep C were reacted to obtain 275 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 MHz):                                                  ______________________________________                                         ##STR119##       5.32 (s)                                                    H.sub.6           5.15                                                        H.sub.7           5.80 (dd, sl after exchange)                                CONH              9.55 (d)                                                     ##STR120##       9.55 (d)                                                     ##STR121##       3.51 (m)                                                     ##STR122##       7.13 (d, J=16) delta E                                       ##STR123##       6.27 (d, t J=16 and 6)                                       ##STR124##       5.67 (d, J=6)                                               H of the thieno pyridine                                                                        7.89 to 9.55                                                aromatics and H.sub.5 thiazole                                                                  6.60 to 6.87 (m)                                            ______________________________________                                    

EXAMPLE 20[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-1,2-dimethylimidazo-[4,5c]-pyridinium trifluoroacetate hydroiodide StepA[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[1-(3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-1,2-dimethylimidazo-[4,5-c]-pyridiniumiodide

1.08 g of the product of Step B of Example 11 were stirred for one hourwith 170 mg of 1,2-dimethyl-4-azabenzimidazole in 0.9 ml of acetonitrileand 40 ml of ether were added. The precipitate was filtered off, rinsedwith ether and dried for 16 hours under reduced pressure to obtain afterchromatography on silica (eluant: methylene chloride--methanol 94-6),306 mg of the expected product.

Step B[3(E),6α,7β(Z)]]-5-[3-[7-[[2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetyl]-amino]2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl[-1,2-dimethylimidazo-[4,5c]-pyridiniumtrifluoro-acetatehydroiodide

Using the procedure of Step B of Example 14, 297 mg of the product ofStep A were reacted to obtain 155 mg of expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 mHz):                                                  ______________________________________                                         ##STR125##       5.40 (sl)                                                    ##STR126##       5.30 (s) 3H                                                 H.sub.6           5.13 (d)                                                    H.sub.7           5.75 (m)                                                     ##STR127##       9.63 (d), 9.65 (d)                                           ##STR128##       6.98 (d, J=15.5) delta E                                     ##STR129##       6.30 (d, t)                                                 the CH.sub.3 's   2.71 (s), 3.92 (s)                                          imidazopyridine   8.28 to 9.48                                                aromatics and H.sub.5 thiazole                                                                  6.66 to 6.85                                                mobile H's        9.00 to 9.08                                                ______________________________________                                    

EXAMPLE 21[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-2,3-dimethylimidazo-[4,5-c]-pyridiniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[1-(3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-2,3-dimethylimidazo-4,5-c]pyridiniumiodide

Using the procedure of Step A of Example 20, 1.92 g of the product ofStep B of Example 11 and 303 mg of 2,3-dimethyl-4-azabenzimidazole werereacted to obtain 877 mg of the expected product.

Step B [6R-[3(E),6α,7β(Z)]]-5-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imido]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-2,3-dimethylimidazo-[4,5-c]-pyridiniumtrifluoroacetate hydroiodide

Using the procedure of Step B of Example 14, 865 mg of the product ofStep A were reacted to obtain 488 mg of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 MHz):                                                  ______________________________________                                         ##STR130##        5.31 (s) 3H                                                 ##STR131##        5.41 (l)                                                   H.sub.6            5.15 (d, resolved)                                         H.sub.7            5.76                                                        ##STR132##        9.53 (d), 9.60 (d)                                          ##STR133##        (d, J=15.5) delta E                                         ##STR134##        6.34 (d, t)                                                the CH.sub.3 's    2.75 (s), 3.94 (s)                                         imidazopyridine    8.18 to 9.58                                               aromatics and H.sub.5 thiazole                                                                   6.65 to 6.86                                               mobile H's         7.31 to 9.60                                               ______________________________________                                    

EXAMPLE 22[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinoliniumtrifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[1-(3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-[(diphenyl-methoxy)-2-oxoethoxy]-imino][2-[(tribenzyl-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinoliniumiodide

Using the procedure of Step B of Example 6, 2.50 g of the iodinatedderivative of Step B of Example 11 and 0.63 g of quinoline were reactedto obtain 2.40 g of the expected product which was purified bychromatography on silica (eluant: methylene chloride--methanol 95-5).

Step B [6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinoliniumtrifluoroacetate hydroiodide

Using the procedure of Step B of Example 14, 1.65 g of the product ofStep A were reacted to obtain 0.94 g of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 MHz):                                                  ______________________________________                                         ##STR135##       5.31 (s)                                                    H.sub.6           5.14 (d)                                                    H.sub.7           5.75 (m)                                                     ##STR136##       9.48 (d), 9.52 (d)                                           ##STR137##       6.97 (d, J=15) delta E                                       ##STR138##       5.89 (m)                                                    H of the quinoline                                                                              8.07 to 9.59                                                aromatics and H.sub.5 thiazole                                                                  6.64 to 6.77; 6.85 (s)                                      mobile H's        9.03 to 9.52                                                ______________________________________                                    

EXAMPLE 23[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-4-ethylthiopyridinium trifluoroacetate hydroiodide Step A[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[1-(3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-[(diphenyl-methoxy)-2-oxoethoxy]-imino]-[2-[(tribenzyl)-amino]-4-thiazolyl]-acetamido]-2-[(p-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3yl]-2-propenyl]-4-ethylthiopyridinium iodide

Using the procedure of Step B of Example 6, 2.50 g of the iodinatedderivative of Step B of Example 11 and 1 ml of 4-ethylthio pyridine werereacted to obtain 2.45 g of the expected product which was purified bychromatography on silica (eluant: methylene chloride--methanol 95-5).

Step B[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxy-phenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-4-ethylthiopyridinium trifluoroacetate hydroiodide

Using the procedure of Step B of Example 14, 1.54 g of the product ofStep A were reacted to obtain 0.807 g of the expected product.

    ______________________________________                                        NMR Spectrum (DMSO 400 MHz):                                                  ______________________________________                                         ##STR139##       5.32 (s)                                                    H.sub.6           5.16                                                        H.sub.7           5.77 (m)                                                     ##STR140##       9.47 (d)                                                     ##STR141##       6.98 (d, J=16) delta E                                       ##STR142##       6.26 (d, t)                                                 H of the pyridine 7.97 to 8.69                                                aromatics and H.sub.5 thiazole                                                                  6.67 to 6.78; 6.87 (s)                                      mobile H's        9.04 to 13.80                                               ______________________________________                                    

EXAMPLE 24 The internal salt of [6R-[3(E),6α,7β(Z)]]7-[3-[7-[[(2-amino4-thiazolyl) [carboxy (3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]furo[2,3-b]pyridinium (R) or(S) or an (R+S) mixture Stage A p-methoxy benzyl [6R-[3(E), 6alpha,7beta(Z)]]7-[[[(diphenylmethoxy carbonyl) [3,4-bis[(2-methoxy ethoxy)methoxy]phenyl]methoxy]imino][2-[(triphenylmethyl)amino]4-thiazolyl]acetyl]amino]3-(3-chloro1-propenyl) 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl-2-carboxylate

A suspension of 3.75 g of [[(diphenylmethoxy-carbonyl)[3,4-bis[(2-methoxy ethoxy)methoxy]phenyl]methoxy]imino][2-[(triphenylmethyl)amino]4-thiazolyl]aceticacid syn isomer (described in European Patent EP 238,061) and 1.81 g ofp-methoxy-benzyl 7-amino-3-(3-chloropropenyl) 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-2-carboxylate (prepared in European PatentEP 0 333,154) in dichloromethane was cooled down to 0° C., and 0.920 gof N-(dimethylaminopropyl) N'-ethyl carbodiimide hydrochloride wereadded. The solution was held at 0° C. with stirring for 30 minutes andthe organic phase was washed with an aqueous solution of sodium chlorideand dried. The solvents are eliminated and after chromatographing theresidue on silica (eluant: methylene chloride--ether 85-15) andconcentration in isopropyl ether, 4.546 g of the expected product wereobtained.

NMR (CDCl₃ 400 MHz in ppm) 5.10 to 5.32: CO₂ --CH₂ --Ar (Ar: aromaticring); 3.80: Ar--O--CH₃.

Stage B p-methoxy benzyl [6R-[3(E), 6-α, 7-β(Z)]]7-[[[[(diphenylmethoxycarbonyl) [3,4-bis[(2-methoxy ethoxy)methoxy]phenyl]methoxy]imino][2-triphenylmethyl)amino]4-thiazolyl]acetamido]3-(3-iodo1-propenyl) 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl-2-carboxylate

A mixture of the product of Step A, 10 ml of acetone and 341 mg ofsodium iodide and approximately 10 mg of iodine was stirred for one hourat ambient temperature and the solvent was evaporated off. Then, theresidue was taken up in 80 ml of dichloromethane. The organic phase waswashed with an aqueous solution of sodium thiosulfate then with water.After drying, the solvents were eliminated and the residue waschromatographed on silica [eluant: dichloromethane--ethyl acetate (8-2)]to obtain 853 mg of the expected product.

NMR of the proton, (CDCl₃ 300 MHz) 6.9 to 7.35: --CH═CH--CH₂ --I, Ar--H;6.13 (d,t J=15 and 8): --CH═CH--CH₂ --I, E isomerism; 4.0 (d):--CH═CH--CH₂ --I.

Stage C (±)(cis)(Z) 7-[3-[7-[[(2-amino 4-thiazolyl) [carboxy 8-oxo5-thia1-azabicyclo[4,2,0-oct-2-en-3-yl]2(E)-propenyl]furo[2,3-b]-pyridiniumiodide

1.928 g of the product prepared in Step B, 0.365 g offuro[2,3-b]pyridine and 2 ml of dichloromethane were stirred for twohours and 30 minutes and 40 ml of sulfuric ether were added. Theprecipitate was isolated, rinsed with ether, dried and chromatographedon silica eluting with a dichloromethane--methanol (92-8) mixture toobtain 0.5106 g of the expected product with a Rf=0.38.

NMR of the proton (CDCl₃, 400 MHz, in ppm) 3.22 (s), 3.29 (s) and 3.35(s): --O--CH₂ --O--CH₂ --CH₂ --O--CH₃ ; 3.79 (s): Ar--OCH₃ ; 3.10 to3.9: --S--CH₂ --C(CH═CH--)═C-- and --O--CH₂ --O--CH₂ --CH₂ --O--CH₃ ;5.00 (d) and 5.04 (d): --CO--NH--CH(C═O)--CH(N--)--S--; 5.15 to 5.35:--O--CH₂ --O--CH₂ --CH₂ --O--CH₃ ; 5.32 (s): --(C═O)--O--CH₂ --Ar; 5.79(dd) and 5.85 (dd): --CO--NH--CH(C═O)--CH(N--)--S--; 5.99 (resolved):Ar--CH(C═O)--O--; 6.34 (m): --CH═CH--CH₂ --N⁺ ; 6.77 (resolved):--S--CH--C(C═N--)--N═; 6.84 to 7.34: Ar--H, --CH═CH--CH₂ --N⁺ and the Hin position 3 of the furo[2,3-b]pyridinium; 7.87 (m): H in position 5 ofthe furo[2,3-b]pyridinium 8.03; (m): H in position 2of thefuro[2,3-b]pyridinium 8.15 (d): the --NH--'s; 8.66 (m): H in positions 4and 6 of furo[2,3-b]pyridinium.

Stage D The internal salt of [6R-[3(E), 6-α, 7-β(Z)]] 7-[3-[7-[[(2-amino4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]furo[2,3-b]-pyridinium (R)or (S) or an (R+S) mixture

0.516 g of the product of Step C and 5.1 ml of a solution oftrifluoroacetic acid with 10% anisole were stirred for 75 minutes andthen 30 ml of sulfuric ether were added. The mixture was stirred for 90minutes, followed by filtering, rinsing and drying to obtain 0.261 g ofthe desired product.

NMR of the proton (DMSO, 400 MHz, in ppm) 3.50 to 3.78 (m): --S--CH₃--C(CH═CH--)═C--; 5.16 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--;5.31 (s): Ar--CH(C═O)--O--; 5.58 (m): --CH═CH--CH₂ --N⁺ ; 5.77 (m):--CO--NH--CH(C═O)--CH(N--)--S--; 6.32 (m): --CH═CH--CH₂ --N⁺ ; 6.65 to6.80 (m): aromatic H's of the (3,4-dihydroxy phenyl) (Ar--H); 6.85 (s):--S--CH--C(C═N--)--N═; 7.07 (d resolved): --CH═CH--CH₂ --N⁺ ; 7.52 (d):H in position 3 of the furo[2,3-b]pyridinium 7.98; (dd): H in position 5of the furo[2,3-b]pyridinium 8.61 (d): H in position 2 of thefuro[2,3-b] pyridinium 8.89 (dl) and 8.93; (d): H in positions 4 and 6of the furo[2,3-b]pyridinium; 7.31 (sl) (2H) and 9.04 (m) (2H): mobileH's; 9.53 (d) and 9.61 (d): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 25 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]7-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]furo[3,2-b]-pyridinium (R)or (S) or an (R+S) mixture

Using the procedure of Example 24, furo[3,2-b]pyridine as quaternizationagent was reacted to obtain the desired product.

NMR of the proton (DMSO, 400 MHz, in ppm) --S--CH₂ --C(CH═CH--)═C--masked; 5.14 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--; 5.32 (s):Ar--CH(C═O)--O--; 5.61 (m): --CH═CH--CH₂ --N⁺ ; 5.76 (m):--CO--NH--CH(C═O)--CH(N--)--S--; 6.30 (m): --CH═CH--CH₂ --N⁺ E isomer;6.6 to 6.78 (m): Ar--H; 6.86 (s): --S--CH--C(C═N--)--N═; 7.02 (dresolved): --CH═CH--CH₂ --N⁺ ; 7.82 (sl): H in position 3 of thefuro[3,2-b]pyridinium 8.06; (dd): H in position 6 of thefuro[3,2-b]pyridinium 8.92 (d): H in position 2 of thefuro[3,2-b]pyridinium 8.97 (d) to 9.04; (m): H in positions 5 and 7 ofthe furo[ 3,2-b]pyridinium; 9.0 (m): mobile H's; 9.48 (d) and 9.56 (d):--CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 26 The internal salt of (S)(cis)(Z) 7-[3-[7-[(2-amino4-thiazolyl)[[carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]thieno[2,3-b]pyridinium

Using the procedure of Example 24, -[[(S)-(diphenylmethoxycarbonyl)[3,4-bis[(2-methoxyethoxy)methoxy]phenyl]methoxy]imino][2-[(triphenylmethyl)amino]4-thiazolyl]acetic acid syn isomer (described in European Patents EP 0 266,060 and 0280,521) and thieno[2,3-b]pyridine as quaternization agent were reactedto obtain the desired product with Rf=0.5 [thin layer chromatography(TLC); eluant: acetone--water (4-1)] and a specific rotation of [α]_(D)=-11.5° [(c)=0.9 in DMSO].

NMR of the proton (DMSO, 400 MHz, in ppm) 3.51 (m): --S--CH₂--C(CH═CH--)═C--; 5.15 (d J=5); --CO--NH--CH(C═O)--CH(N--)--S--; 5.32(s): Ar--CH(C═O)--O--; 5.67 (d, J=6): --CH═CH--CH₂ --N⁺ ; 5.8 (dd, slafter exchange): --CO--NH--CH(C═O)--CH(N--)--S--; 6.27 (dt J=16 and 6):--CH═CH--CH₂ --N⁺ E isomer; 6.6 to 6.87 (m): Ar--H and--S--CH--C(C═N--)--N═; 7.13 (d J=6): --CH═CH--CH₂ --N⁺ ; 7.89 (d): H inposition 3 of the thieno[2,3-b]pyridinium 8.15 (dd): Hin position 5 ofthe thieno[2,3-b]pyridinium 8.28 (d): H in position 2 of thethieno[2,3-b]pyridinium 9.08 (d): H in position 4 of thethieno[2,3-b]pyridinium 9.22 (d): H in position 6 of thethieno[2,3-b]pyridinium 9.55 (d): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 27 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]4-methoxy pyridinium (R) or(S) or an (R+S) mixture

By operating in a similar manner to that of Example 1, using 4-methoxypyridine as quaternization agent, the desired product is obtained.

NMR of the proton (DMSO, 400 MHz, in ppm) 3.72 (AB): --S--CH₂--(CH═CH--)═C--; 4.10 (s): Ar--O--CH₃ ; 5.15 (d):--CO--NH--CH(C═O)--CH(N--)--S--; 5.22 (l): --CH═CH--CH₂ --N⁺ ; 5.32 (s):Ar--CH(C═O)--O--; 5.77 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 6.25 (m):--CH═CH--CH₂ --N⁺ E isomer; 6.68 (dd), 6.74 (m) (2H) and 6.86 (s) (1H)═:Ar--H and --S--CH--C(C═N--)--N═; 6.95 (d J=15.5): --CH═CH--CH₂ --N⁺ ;7.33: NH₂ ; 7.66 (d) and 8.83 (m): aromatic H's of 4-MeO pyridinium; 9.0(l), 9.5 (d) and 9.62 (d): mobile H's.

EXAMPLE 28 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]4-(methylthio) pyridinium(R+S)

By operating in a similar manner to that of Example 1, using4-methylthio) pyridine as quaternization agent, the desired product isobtained.

NMR of the proton (DMOS, 300 MHz, in ppm) 2.72 (s): Ar--S--CH₃ ; 5.15(d) and 5.18 (d): --CO--NH--CH(C═O)--CH(N--)--S--; 5.22 (dl):--CH═CH--CH₂ --N⁺ ; 5.32 (s): Ar--CH(C═O)--O--; 5.77 (m, d resolvedafter exchange): --CO--NH--CH(C═O)--CH(N--)--S--; 6.26 (m): --CH═CH--CH₂--N⁺ isomer; 6.65 (dd) to 6.87 (m) (4H)═: Ar--H and--S--CH--C(C═N--)--N═; 6.99 (d J=15 Hz): --CH═CH--CH₂ --N⁺ ; 7.96 (d)and 8.70 (d): aromatic H's of 4-Mes pyridinium; 9.55 (d) and 9.62 (d):--CO--NH--CH(C═O)--CH(N--)--S--; 7.32 (m) and 9.06 (m): mobile H's.

EXAMPLE 29 The internal salt of [6R-[3(E), 6 -α,7-β[Z-(R⁺)]]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]4-(methylthio) pyridinium

Using the procedure of Example was purified by HPLC on a MicrobondapackC₁₈₋₃₀₀ (registered trademark) column of 10 microns and 0.019 m indiameter eluting with acetonitrile with 0.025% trifluoroacetic acid toobtain the (R) and (S) isomers (See following example).

NMR of the proton (DMSO, 300 MHz, in ppm) 2.71 (s): Ar--S--CH₃ ; 3.54(d) and 3.79 (d): --S--CH₂ --C(CH═CH--)═C--; 5.17 (d):--CO--NH--CH(C═O)--CH(N--)--S--; 5.22 (l): --CH═CH--CH₂ --N⁺ ; 5.32 (s):Ar--CH(C═O)--O--; 5.77 (d, d): --CO--NH--CH(C═O)--CH(N--)--S--; 6.27(m): --CH═CH--CH₂ --N⁺ E isomer; 6.72 (d): H in position 5 of the(3,4-dihydroxy phenyl); 6.74 (s): --S--CH--C(C═N--)--N═; 6.73 (d): H inposition 6 of the (3,4-dihydroxy phenyl); 6.86 (d): H in position 2 ofthe (3,4-dihydroxy phenyl); 6.98 (d J=15,5 Hz): --CH═CH--CH₂ --N⁺ ; 7.30(l): --NH ₂ ; 7.96 (d) and 8.71 (d): aromatic H's of 4-MeS pyridinium;9.62 (d): --CO--NH--CH(C═O)--CH(N--)--S--; 9.00 and 9.09: mobile H's.

EXAMPLE 30 The internal salt of [6R-[3(E), 6-α,7-β[Z-(S⁺)]]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]4-(methylthio) pyridinium

NMR of the proton (DMSO, 300 MHz, in ppm) 2.72 (s): Ar--S--CH₃ ; 3.54[AB]: --S--CH₂ --C(CHαCH--)═C--; 5.14 (d):--CO--NH--CH(C═O)--CH(N--)--S--; 5.22 (dl): --CH═CH--CH₂ --N⁺ ; 5.32(s): Ar--CH(C═O)--O--; 5.79 (dd): --CO--NH-CH(C═O)--CH(N--)--S--; 6.24(dt): --CH═CH--CH₂ --N⁺ E isomer; 6.65 to 6.78 (m) (3H) and 6.87 (1H):Ar--H and --S--CH(C═N--)--N═; 6.97 (d): --CH═CH--CH₂ --N⁺ ; 7.30 (l):--NH₂ ; 7.96 (d) and 8.70 (d): aromatic H's of 4-MeS pyridinium; 9.55(d): --CO--NH--CH(C═O)--CH(N--)--S--; 9.04 and 9.08: mobile H' s.

EXAMPLE 31 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [[carboxy (3,4-dihydroxyphenyl)methoxy]imino]acetyl]amino]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]2-(methylthio) pyridinium(R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 2.87 (s): Ar--S--CH₃ ; 5.16(d, resolved): --CO--NH--CH(C═O)--CH(N--)--S--; 5.78 (d, resolved afterexchange): --CO--NH--CH(C═O)--CH(N--)--S--; 6.13: --CH═CH--CH₂ --N⁺ Eisomer; 6.65 to 6.80: Ar--H; 6.85: --S--CH(C═N--)--N═; 6.85 (Dresolved): --CH═CH--CH₂ --N⁺ ; 7.32 and 9.05: --OH; 7.84 (t) and 8.44(t): aromatic H's in position 3 and 4 of the 2-Mes pyridinium; 8.04 (d):aromatic H in position 5 of the 2-MeS pyridinium; 8.97 (d): aromatic Hin position 2 of the 2-Mes pyridinium; 9.57 (d resolved):--CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 32 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]4-(aminocarbonyl) pyridinium(R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.50 to 3.75 (m): --S--CH₂--C(CH═CH--)═C--; 5.17 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--;5.32 (s): Ar--CH(C═O)--O--; 5.44 (m): --CH═CH--CH₂ --N⁺ ; 5.77 (m):--CO--NH--CH(C═O)--CH(N--)--S--; 6.29 (m): --CH═CH--CH₂ --N⁺ E isomer;6.66 to 6.78 (m) (3H): Ar--H; 6.86 (s): --S--CH(C═N--)--N═; 7.06 (d,J=15.5): --CH═CH--CH₂ --N⁺ ; 8.44 (d): H in positions 3 and 5 of thepyridinium ring; 8.67 (s) and 8.25 (s): (C═O)--NH₂ slightly mobile; 9.20(d): H in positions 2 and 6 of the pyridinium ring; 9.47 (d) and 9.54(d): --CO--NH--CH(C═O)--CH(N--)--S--; 8.94 (m) (2H) 7.24 (m) (2H) and12.85 (shoulder): mobile H's.

EXAMPLE 33 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]3-(aminocarbonyl) pyridinium(R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.50 to 3.80 (m): --S--CH₂(CH═CH--)═C-- masked; 5.17 (d resolved):--CO--NH--CH(C═O)--CH(N--)--S--; 5.32 (s): Ar--CH(C═O)--O--; 5.44 (m):--CH═CH--CH₂ --N⁺ ; 5.77 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 6.30 (m):--CH═CH--CH₂ --N⁺ E isomer; 6.64 to 6.90 (m) (4H): Ar--H and--S--CH(C═N--)--N═; 7.08 (d J=15): --CH═CH--CH₂ --N⁺ ; 7.29 (3H):═C--NH₂ ; 8.29 (t): H in position 5 of the pyridinium ring; 8.36 (d): Hin position 4 of the pyridinium ring; 9.17 (d): H in position 6 of thepyridinium ring; 9.47 (d): H in position 2 of the pyridinium ring; 9.54(d) and 9.62: --CO--NH--CH(C═O)--CH(N--)--S--; 8.20 (s) and 8.61 (s):slightly mobile H's 9.02: mobile H's.

EXAMPLE 34 The internal salt of [6R-[3(E), 6-α, 7-β(Z)]]6-amino1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy (3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]quinolinium (R) or (S) or an(R+S) mixture

NMR of the proton (DMSO, 400 MHz, in ppm) 5.13:--CO--NH--CH(C═O)--CH(N--)--S--; 5.31 (d resolved): Ar--CH(C═O)--O--;5.65 to 5.80: --CH═CH--CH₂ --N⁺ and --CO--NH--CH(C═O)--CH(N--)--S--;6.32 (m): --CH═CH--CH₂ --N⁺ E isomer; 6.65 to 7.0 (m) (5H): Ar--H,--S--CH--C(C═N--)--N═ and --CH═CH--CH₂ --N⁺ ; 7.56 (d resolved): H inposition 7 of the quinolinium ring; 7.88 (m): H in position 3 of thequinolinium ring; 8.19 (m): H in position 8 of the quinolinium ring;8.80 (d): H in position 4 of the quinolinium ring; 9.0 (s): 9.53 (d) and9.61 (d): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 35 The internal salt of [6R-[3(E), 6-α, 7-β(Z)]]3-amino1-[3-[7-[[(2-amino 4-thiazolyl)[carboxy (3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]quinolinium (R) or (S) or an(R+S) mixture NMR of the proton (DMSO, 300 MHz, in ppm) 5.14:--CO--NH--CH(C═O)--CH(N--)--S--; 5.31 (s) and 5.32 (s):Ar--CH(C═O)--O--; 5.60 to 5.85 (m): --CH═CH--CH₂ --N⁺ and--CO--NH--CH(C═O) --CH(N--)--S--; 6.33 (m): --CH═CH--CH₂ --N⁺ E isomer;6.6 to 6.8 (m): Ar--H, 6.86 (s): --S--CH--C(C═N--)--N═; 6.98 (dresolved): --CH═CH--CH₂ --N⁺ ; 7.76 (m) (2H), 8.1 (m) (1H) and 8.25 (m)(1H): H in positions 5, 6, 7 and 8 of the quinolinium ring; 8.03 (d): Hin position 4 of the quinolinium ring; 8.87 (sl): H in position 2 of thequinolinium ring; 9.09 (m): mobile H's; 9.53 (d) and 9.61 (d):--CO--NH--CH(C═O)--CH(N--)--S--. EXAMPLE 36 The internal salt of[6R-[3(E), 6-α, 7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl)[carboxy(3,4-dihydroxy phenyl)methoxy]imino]acetamido]2-carboxy 8-oxo5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]3-methyl quinolinium(R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 2.66 (s): --CH₃ in position 3of the quinolinium ring; 3,50 (masked) and 3.75 (d): --S--CH₂(CH═CH')═C--; 5.13 resolved: --CO--NH--CH(C═O)--CH(N--)--S--; 5.31 (s):Ar--CH(C═O)--O--; 5.78 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 5.85 (m):HCH═CH--CH₂ --N⁺ ; 6.36 (m): --CH═CH--CH₂ --N⁺ E isomer; 6.62 to 6.8 (m)(3H): Ar--H; 6.85 (s): --S--CH--C(C═N--)--N═; 7.00 (d resolved):--CH═CH--CH₂ --N⁺ ; 8.01 (t) and 8.19 (t): H in position 6 and 7 of thequinolinium ring; 8.38 (d) and 8.50 (d): H in position 5 and 8 of thequinolinium ring; 9.14 (sl) and 9.54 (sl): H in position 2 and 4 of thequinolinium ring; 9.04 (m): mobile H's; 9.53 (d) and 9.59 (d):--CO--NH--CH(C═O)--CH(N--)--S--;

EXAMPLE 37 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8 -oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]4-methyl quinolinium (R) or(S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.02 (s): --CH₃ in position 4of the quinolinium ring 3.45 to 3.80 (m): --S--CH₂ --C(CH═CH--)═C--;5.13 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--; 5.31 (s):Ar--CH(C═O)--O--; 5.75 (d, resolved after exchange):--CO--NH--CH(C═O)--CH(N--)--S--; 5.80 (m): --CH═CH--CH₂ --N⁺ ; 6.37 (m):--CH═CH--CH₂ --N⁺ E isomer approximately 6.70 (m) (3H): Ar--H; 6.85 (s):--S--CH--C(C═N--)--N═; 6.96 (d resolved j=16 Hz): --CH═CH--CH₂ --N⁺ ;8.06 (t) and 8.25 (t): H in position 6 and 7 of the quinolinium ring;8.11 (d): H in position 3 of the quinolinium ring; 8.50 (2d): H inposition 5 and 8 of the quinolinium ring; 9.43 (d): H in position 2 ofthe quinolinium ring; 7.30 (sl and 9.03 (sl): mobile H's (--NH₂ and--OH); 9.51 (d) and 9.59 (d): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 38 The internal salt of [6R-[3(E), 6-α, 7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]6-methyl quinolinium (R) or(S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 2.62 (s): --CH₃ in position 4of the quinolinium ring 3.50 (masked) and 3.74 (d): --S--CH₂--(CH═CH--)═C--; 5.13 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--;5.31 (s): Ar--CH(C═O)--O--; 5.76 (d, resolved after exchange):--CO--NH--CH(C═O)--CH(N--)--S--; 5.86 (m): --CH═CH--CH₂ --N⁺ ; 6.35 (m):--CH═CH--CH₂ --N⁺ E isomer; 6.85 (s resolved): --S--CH--C(C═N--)--N═;6.94 (d resolved j=16 Hz): --CH═CH--CH₂ --N⁺ ; 8.10 to 8.45 (m) (4H): Hin position 3, 5, 7 and 8 of the quinolinium ring; 9.21 (d) (1H): H inposition 4 of the quinolinium ring; 9.50 (d): H in position 2 of thequinolinium ring; 9.03 (m): mobile H's; 9.50 (d) and 9.60 (d):--CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 39 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]6-chloro quinolinium (R) or(S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.60 (masked) and 3.75 (d):--S--CH₂ (CH═CH--)═C--; 5.14: --CO--NH--CH(C═O)--CH(N--)--S--; 5.31 (s):Ar--CH(C═O)--O--; 5.76 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 5.88 (m):--CH═CH--CH₂ --N⁺ ; 6.34 (m): --CH═CH--CH₂ --N⁺ E isomer; 6.85 (s):--S--CH--C(C═N--)--N═; 6.96 (d resolved): --CH═CH--CH₂ --N⁺ ; 6.62 to6.80 (m) (3H): Ar--H; 8.29 (m) and 8.59 (dd): H in positions 3, 7 and 8of the quinolinium ring; 8.69 (d): H in position 5 of the quinoliniumring; 9.25 (d): H in position 4 of the quinolinium ring; 9.59 (d): H inposition 2 of the quinolinium ring; 9.04 (m): mobile H's; 9.52 (d) and9.60 (d): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 40 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl)[carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-yl]2-propenyl]6-methoxy quinolinium (R) or(S) or an (R+S) mixture NMR of the proton (DMSO, 400 MHz, in ppm) 3.45to 3.75 (m): --S--CH₂ --C(CH═CH--)═C--; 4.00 (s): --OCH₃ in position 6of the quinolinium ring; 5.12 (d resolved):--CO--NH--CH(C═O)--CH(N--)--S--; 5.31 (s): Ar--CH(C═O)--O--; 5.74 (ddresolved): --CO--NH--CH(C═O)--CH(N--)--S--; 5.84 (m): --CH═CH--CH₂ --N⁺; 6.35 (m): --CH═CH--CH₂ --N⁺ E isomer; 6.65 to 6.80 (m): Ar--H; 6.85(s): --S--CH--C(C═N--)--N═; 6.93 (d resolved J=16 Hz): --CH═CH--CH₂ --N⁺; 7.89 (dd): H in position 7 of the quinolinium ring; 7.90 (sl): H inposition 5 of the quinolinium ring; 8.15 (dd): H in position 3 of thequinolinium ring; 8.46 (dd): H in position 4 of the quinolinium ring;9.13 (d): H in position 8 of the quinolinium ring; 9.37 (d): H inposition 2 of the quinolinium ring; 7.29 (m) (2H) and 8.94 (m) (2H):mobile H's; 9.45 (d) and 9.52 (d): --CO--NH--CH(C═O)--CH(N--)--S.EXAMPLE 41 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]3-[3-[7-[[(2-amino 4-thiazolyl)[carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]thiazolium (R) or (S) or an(R+S) mixture

NMR of the proton (DMSO, 400 MHz, in ppm) 3.40 3.80 (m): --S--CH₂--C(CH═CH--)═C--; 5.16 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--;5.33 (m) (3H: Ar--CH(C═O)--O-- and --CH═CH--CH₂ --N⁺ ; 5.77 (m):--CO--NH--CH(C═O)--CH(N--)--S--; 6.26 (m): --CH═CH--CH₂ --N⁺ E isomer;6.65 to 6.77 (m): Ar--H; 6.87 (s): --S--CH--C(C═N--)--N═; 6.97 (dresolved): --CH═CH--CH₂ --N⁺ ; 7.30 (s) (2H): mobile H's; 8.36 (s) and8.52 (s): H in position 4 and 5 of the thiazolium ring 9.00 (s), 9.08(s), 9.09 (s) and 9.64 (s): mobile 2H's; 9.54 (d) and 9.62 (d):--CO--NH--CH(C═O)--CH(N--)--S--; 10.21 (s): H in position 2 of thethiazolium ring.

EXAMPLE 42 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl)[carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]3-methyl imidazolium (R) or(S) or an (R+S) mixture

NMR of the proton (DMSO, 40 MHz, in ppm) 3.50 to 3.80: --S--CH₂--C(CH═CH--)═C--; 3.86 (s): --CH₃ in position 3 of the imidazolium ring;4.97 (d): --CH═CH--CH₂ --N⁺ ; 5.16 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--; 5.33 (s): Ar--CH(C═O)--O--; 5.79 (m):--CO--NH--CH(C═O)--CH(N--)--S--; 6.18 (m): --CH═CH--CH₂ --N⁺ E isomer;6.75 to 7.00 (m): Ar--H, --S--CH--C(C═N--)--N═ and --CH═CH--CH₂ --N⁺ ;7.28: NH₂ ; 7.71 (s) (2H): H in position 2 and 3 of the imidazolium ring8.96 (wide), 12.81 (wide) and 13.68 (wide): mobile 2H's 9.12; (s): H inposition 5 of the imidazolium ring; 9.47 (d) and 9.54 (d):--CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 43 The internal salt of (±)(cis)(Z) 1-[-3-[7-[[(2-amino4-thiazolyl) [carboxy(3,4-dihydroxy phenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]-oct-2-en-3-yl]2(E)-propenyl]imidazo[1,2-b]pyridazinium (R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 400 MHz, in ppm) (1H) masked and approximately3.70 (d) (1H): --S--CH₂ --C(CH═CH--)═C--; 5.15 (d resolved):--CO--NH--CH(C═O)--CH(N--)--S--; 5.25 to 5.45 (m): --CH═CH--CH₂ --N⁺ andAr--CH(C═O)--O--; 5.77 (m, d resolved after exchange):--CO--NH--CH(C═O)--CH(N--)--S--; 6.25 (m): --CH═CH--CH₂ --N⁺ E isomer;6.65 to 6.86 (m): Ar--H and --S--CH--C(C═N--)--N═; 6.96 (dl J=16 Hz):--CH═CH--CH₂ --N⁺ ; 7.34 (m) and 9.05 (m): mobile H's; 8.00 (dd): H inposition 3 of the imidazo[1,2-b]pyridazinium ring; 8.54 (sl) and 8.88(sl): H in position 6 and 7 of the imidazo[1,2-b]pyridazinium ring; 8.82(d): H in position 4 of the imidazo[1,2-b]pyridazinium ring; 9.12 (d): Hin position 2 of the imidazo[1,3-b]pyridazinium ring; 9.55 (d) and 9.60(d): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 44 The internal salt of (±)(cis)(Z) 1-[3-[7-[[(2-amino4-thiazolyl) [carboxy(3,4-dihydroxy phenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]imidazo[1,2-a]pyridinium(R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.55 (m) (masked): --S--CH₂--C(CH═CH--)═C--; 5.15 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 5.29 (m):--CH═CH--CH₂ --N⁺ ; 5.32 (s): Ar--CH(C═O)--O--; 5.74 (m):--CO--NH--CH(C═O)--CH(N--)--S-- cis isomerism; 6.25 (m): --CH═CH--CH₂--N⁺ E isomer; 6.68 to 6.92: Ar--H, --S--CH--C(C═N--)--N═ and--C═CH--CH₂ --N⁺ ; 7.33 (s), 9.03 (s), 9.56 (d resolved) and 123.80:mobile H's; 7.57 (t) (1H), 8.06 (t) (1H), 8.20 (d) (1H), 8.29 (s) (1H),8.45 (s) (1H) and 8.97 (d) (1H): H of the imidazo [1,2-b]-pyridiniumring.

EXAMPLE 45 The internal salt of (±)(cis)(Z) 2-[3-[7-[[(2-amino4-thiazolyl) [carboxy(3,4-dihydroxy phenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]imidazo-[1,5-a]pyridinium(R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.40 to 3.80: --S--CH₂--C(CH═CH--)--C--; 5.17 (m): -CO--NH--CH(C═O)--CH(N--)--S--; 5.18 to5.32: --CH═CH--CH_(2l) --N⁺ and Ar--CH(C═O)--O--; 5.76 (m):--CO--NH--CH(C═O)--CH(N--)--S-- cis isomerism; 6.28 (m): --CH═CH--CH₂--N⁺ E isomer; 6.68 to 6.86: Ar--H and --S--CH--C(C═N--)--N═; 7.04 (dJ=15.5): --CH═CH--CH₂ --N⁺ ; 7.29, 9.0 to 9.08, 9.54 and 12.56: mobileH's; 7.19 (t) and 7.25 (t): H in position 6 and 7 of the imidazo[1,5-a]pyridinium ring; 7.86 (d): H in position 8 of the imidazo[1,5-a]pyridinium rings; 8.23 (d): H in position 1 of theimidazo[1,5-a]pyridinium ring; 9.02 (d): H in position 5 of the imidazo[1,5-a]pyridinium ring; 9.74 (s): H in position 3 of the imidazo[1,5-a]pyridinium ring.

EXAMPLE 46 The internal salt of [6R-[3-(E), 6-α, 7-62[Z(R⁺)]]]1-[3-[7-[[(2-amino 4-thiazolyl)[carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]6,7-dihydro5H-pyridinium, Stage A The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[[[[(diphenylmethoxycarbonyl)[3,4-bis[(2-methoxyethoxy)methoxy]phenyl]methoxy]imino][2-(tri-phenylmethyl)amino]4-thiazolyl]acetamido]2 -carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]6,7-dihydro5H-pyridinium, (R+S)

1.33 g of the iodine derivative of Step B of Example 24 and 0.585 ml ofcyclopentano[b]pyridine in a minimum quantity of dimethylsulfoxide(DMSO) were stirred for 5 hours and the solvent was eliminated. Theresidue was washed and chromatographed, eluting with adichloromethane--methanol (9-1) mixture to obtain in this way 1.07 g ofthe desired product.

Stage B The internal salt of [6R-[3(E), 6-α, 7-β(Z)]]1-[3-[7-[[(2-amino4-thiazolyl)[carboxy (3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]6,7-dihydro 5H-pyridinium

Using the procedure of Step D of Example 24, 1.053 g of the product ofStep A were reacted to obtain 1.07 g of the expected product.

Stage C The internal salt of [6R-[3(E), 6-α,7-β[Z(R⁺)]]]1-[3-[7-[[(2-amino 4-thiazolyl)[carboxy(3,4-dihydroxyphenyl) methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]6,7-dihydro5H-pyrindinium

The product of Step B was purified by HPLC on a Microbondapack C₁₈₋₃₀₀(registered trademark) column of 10 microns and 0.0079 m in diametereluting with acetonitrile with 0.025% of trifluoroacetic acid to obtainthe (R) and (S) isomers (See following example.

NMR of the proton (DMSO, 400 MHz, in ppm) 2.24 (m): the H's in position5 of the 6,7-dihydro 5H-pyrindinium ring; 3.15 (m) and 3.38 (masked):the H's in position 5 and 7 of the 6,7-dihydro 5H-pyridinium ring; 3.54(d, J=17.5 Hz) and 3.78 (d, J=17.5 Hz): --S--CH₂ --C(CH═CH--)═C--; 5.17(d, J=5): --CO--NH--CH(C═O)--CH(N--)--S--; 5.32 (m): --CH═CH--CH₂ --N⁺and Ar--CH(C═O)--O--; 5.75 (dd, J=5 Hz and J=7.5 Hz):--CO--NH--CH(C═O)--CH(N--)--S--; 6.24 (dt, J=16 and J=6.5 Hz):--CH═CH--CH₂ --N⁺ E isomer; 6.70 (d, J=8 Hz): H in position 6 of the3,4-dihydroxyphenyl radical; 6.74 (s): --S--CH--C(C═N--)--N═; 6.75 (dd,J=1.5 and J=8 Hz): H in position 5 of the 3,4-dihydroxyphenyl radical;6.86 (sl): H in position 2 of the 3,4-dihydroxyphenyl radical 6.87 (dJ=16): --CH═CH--CH₂ --N⁺ ; 7.25: Mobile NH₂ 's; 7.90 (dd, J=6 andJ=7.5): H in position 3 of the 6,7-dihydro 5H-pyrindinium ring; 8.41 (d,J=7.5): H in position 4of the 6,7-dihydro 5H-pyridinium ring; 8.75 (d,J=6): H in position 2of the 6,7-dihydro 5H-pyrindinium ring; 9.53 (d,J=7.5 Hz): --CO--NH--CH(C═O)--CH(N--)--S-- ; 8.92, 9.00, 12.76 and13.72: mobile H's.

EXAMPLE 47 The internal salt of [6R-[3(E), 6-α,7-β[Z(S⁺)]]]2-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]6,7-dihydro5H-pyrindinium,

NMR of the proton (DMSO, 400 MHz, in ppm) 2.24 (m): the H's in position6 of the 6,7-dihydro 5H-pyrindinium ring; 3.15 (m) and 3.40: the H's inposition 5 and 7 of the 6,7-dihydro 5H-pyrindinium ring; 3.48 (d, J=17.5Hz) and 3.63 (d, J=17.5 Hz): --S--CH₂ --C(CH═CH--)═C--; 5.14 (d, J=5);--CO--NH--CH(C═O)--CH(N--)--S--; 5.32 (m): --CH═CH--CH₂ --N⁺ andAr--CH(C═O)--O--; 5.78 (dd, J=5 Hz and J=7.5 Hz):--CO--NH--CH(C═O)--CH(N--)--S--; 6.20 (dt, J=16 and J=6 Hz):--CH═CH--CH₂ --N⁺ E isomer; 6.68 (d, J=8 Hz): H in position 6 of the3,4-dihydroxyphenyl radical; 6.75 (dd, J=2 and J=8 Hz): H in position 5of the 3,4-dihydroxyphenyl radical; 6.78 (s): --S--CH--C(C═N--)--N═;6.87 (d. J=2 Hz): H in position 2 of the 3,4-dihydroxyphenyl radicals6.87 (d J=16): --CH═CH--CH₂ --N⁺ ; 7.25: mobile NH₂ 's; 7.90 (dd, J=6and J=7.5): H in position 3 of the 6,7-dihydro 5H-pyrindinium ring; 8.42(d, J=7.5): H in position 4 of the 6,7-dihydro 5H-pyrindinium ring; 8.75(d, J=6): H in position 2 of the 6,7-dihydro 5H-pyrindinium ring; 9.46(d, J=7.5 Hz): --CO--NH--CH(C═O)--CH(N--)--S--; 8.98 (2H), 9.00, 12.97(1H) and 13.69 (1H): mobile H's.

EXAMPLE 48 The internal salt of [6R-[3(E), 6-α,7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl] 4-[(methoxyimino)methyl]quinolinium (R) or (S) or an (R+S) mixture.

NMR of the proton (DMSO, 300 MHz, in ppm) 3.47 (m): --S--CH₂--C(CH═CH--)═C--; 4.19 (s): --CH═N--OCH₃ in position 4 of thequinolinium ring; 5.14 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 5.31 (s):Ar--CH(C═O)--O--; 5.75 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 5.89 (m):--CH═CH--CH₂ --N⁺ ; 6.36 (m): --CH═CH--CH₂ --N⁺ E isomer; 6.64 to 6.77(m): Ar--H; 6.85 (s,d): --S--CH--C(C═N--)--N═; 6.99 (d resolved j=16Hz): --CH═CH--CH₂ --N⁺ ; 7.31 (l): --NH₂ ; 8.09 (l) and 8.30 (t): H inposition 6 and 7 of the quinolinium rings 8.42 (d): H in position 3 ofthe quinolinium ring; 8.58 (d) and 8.96 (d): H in position 5 and 8 ofthe quinolinium ring 9.33 (s): --CH═N--OCH₃ in position 4 of thequinolinium ring (E isomer); 9.52 (d,d): H in position 2 of thequinolinium ring; 9.03 (l) and 9.60 (d): mobile H's.

EXAMPLE 49 The internal salt of (±)(cis)(Z) 1-[3-[7-[[(2-amino4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl]2(E)-propenyl]1-methyl pyrrolidinium (R) or (S) oran (R+S) mixture,

NMR of the proton (DMSO, 300 MHz, in ppm) 2.10 (sl) and 3.45 (sl): H ofthe pyrrolidinium ring; 2.99 (s): N⁺ --CH₃ ; 3.9 (m): --S--CH₂--C(CH═CH--)═C--; 4.11: --CH═CH--CH₂ --N⁺ ; 5.18 (m):--CO--NH--CH(C═O)--CH(N--)--S--; 5.33 (s): Ar--CH(C═O)--O--; 5.79 (m):--CO--NH--CH(C═O)--CH(N--)--S--; 6.17 (dt): --CH═CH--CH₂ --N⁺ E isomer;6.65 to 6.85: Ar--H and --S--CH--C(C═N--)--N═; 7.05 (d. J=15 Hz):--CH═CH--CH₂ --N⁺.

EXAMPLE 50 The internal salt of [6R-3(E), 6-α, 7-β(Z)]]1-[3]7-[[(2-amino4-thiazolyl)[carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]4-aza 1-azoniabicyclo[2,2,2]octane (R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.14 and 3.35: H of the 4-aza1-=azoniabicyclo[2,2,2]octane ring; 3.5 to 3.95: --S--CH₂--C(CH═CH--)═C--; 4.06: --CH═CH--CH₂ --N⁺ ; 5.20 (d, resolved):--CO--NH--CH(C═O)--CH(N--)--S--; 5.34 (s): Ar--CH(C═O)--O--; 5.80 (d,resolved): --CO--NH--CH(C═O)--CH(N--)--S--; 6.11: --CH═CH--CH₂ --N⁺ Eisomer; 6.7 to 6.90: Ar--H and --S--CH--C(C═N--)--N═; 7.02 (d,resolved): --CH═CH--CH₂ --N⁺ ; 9.10 (d resolved):--CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 51 The internal salt of [6R-[3(E), 6-α, 7-β(Z)]]1-[3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl]2-propenyl]3-hydroxy 4-aza1-azoniabicyclo[2,2,2]octane (R) or (S) or an (R+S) mixture with anRf=0.5 (eluant: acetone--water (4-1) EXAMPLE 52 The internal salt of(±)(cis)(Z) 3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino] acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-3-yl]N,N,N-trimethyl 2(E)-propen-1-aminium (R)or (S) or an (R+S) mixture,

NMR of the proton (DMSO, 300 MHz, in ppm) 2.99 (s) and 3.03 (s): --N⁺(CH₃)₃ ; 4.05: --CH═CH--CH₂ --N⁺ ; 5.16 (d):--CO--NH--CH(C═O)--CH(N--)--S--; 5.33 (s): Ar--CH(C═O)--O--; 5.76 (d):--CO--NH--CH(C═O)--CH(N--)--S--; 6.04 (m): --CH═CH--CH₂ --N⁺ E isomer;6.7 to 6.90: Ar--H and --S--CH--C(C═N--)--N═; 7.04 (d, resolved):--CH═CH--CH₂ --N⁺ ; 9.08 (d resolved): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 53 The internal salt of 6R-[3(E), 6-α, 7-β(Z)]]3-[7-[[(2-amino4-thiazoly)[carboxy (3,4-dihydroxy phenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl] N,N-dimethyl N-(2-hydroxy ethyl)2-propen-1-aminium (R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.05 (s): --N⁺ (CH₃)₂ --CH₂--CH₂ --OH; 3.38 and 3.87: --N⁺ (CH₃)₂ --CH₂ --CH₂ --OH; 4.14 (d):--CH═CH--CH₂ --N⁺ ; 5.19 (d, resolved): --CO--NH--CH(C═O)--CH(N--)--S--;5.80 (d, resolved): --CO--NH--CH(C═O)--CH(N--)--S--; 6.14: --CH═CH--CH₂--N⁺ E isomer; 6.87: --S--CH--C(C═N--)--N═; 6.65 to 6.80: Ar--H; 7.03(d, resolved): --CH═CH--CH₂ --N⁺ ; 7.36 and 9.05: --OH; 9.59 (dresolved): --CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 54 The internal salt of (±)(cis)(Z) N-(2-amino 2-oxo ethyl) 3-[7-[[(2-amino 4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl] N,N-dimethyl 2(E)-propen-1-aminium (R)or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.19 (s): --N⁺ (CH₃)₂ --CH₂--CO--NH₂ ; 4.01 (s): --N⁺ (CH₃)₂ --CH₂ --CO--NH₂ ; 4.27 (d):--CH═CH--CH₂ --N⁺ ; 5.19 (d): --CO--NH--CH (C═O)--CH(N--)--S--; 5.34(s): Ar--CH(C═O)--O--; 5.85 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 6.13:--CH═CH--CH₂ --N⁺ E isomer; 6.72 to 6.80: Ar--H and--S--CH--C(C═N--)--N═; 7.03: --CH═CH--CH₂ --N⁺ ; 7.33, 7.70, 7.94 and9.04: mobile H's; 9.55 (d) and 9.62 (d): --NH--.

EXAMPLE 55 The internal salt of (±)(cis)(Z) 3-[7-[[(2-amino4-thiazolyl)[carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl] N-(cyanomethyl) N,N-dimethyl2(E)-propen-1-aminium (R) or (S) or an (R+S) mixture,

NMR of the proton (DMSO, 300 MHz, in ppm) 3.19 (s): --N⁺ (CH₃)₂ --CH₂--CN; 4.24 (d): --CH═CH--CH₂ --N⁺ ; 4.8 (s): --N⁺ (CH₃)₂ --CH₂ --CN;5.20 (d): --CO--NH--CH(C═O)--CH(N--)--S--; 5.33 (s): Ar--CH(C═O)--O--;5.82 (m): --CO--NH--CH(C═O)--CH(N--)--S--; 6.13 (m): --CH═CH--CH₂ --N⁺ Eisomer; 6.65 to 6.80: Ar--H; 6.87: --S--CH--C(C═N--)--N═; 7.10:--CH═CH--CH₂ --N⁺ ; 7.79 (2H), 9.07 (2H): mobile H's; 9.54 (d):--CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 56 The internal salt of (±)(cis)(Z) 3-[7-[[ (2-amino4-thiazolyl) [carboxy(3,4-dihydroxyphenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]-oct-2-en-3-yl] N,N-dimethylN-[(2-methoxyimino)ethyl]2(E)-propen-1-aminium (R) or (S) or an (R+S)mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.19 (S): --N⁺ (CH₃)₂ --CH₂--CH═N--O--CH₃ ; 3.89 (s): --N⁺ (CH₃)₂ --CH₂ --CH═N--O--CH₃ ; 4.10 to4.30 (m): --CH═CH--CH₂ --N⁺ and --N⁺ (CH₃)₂ --CH₂ --CH═N--O--CH₃ ; 5.20(d): --CO--NH--CH(C═O)--CH(N--)--S--; 5.35 (s): Ar--CH(C═O)--O--; 5.81(m,d resolved after exchange): --CO--NH--CH(C═O)--CH(N--)--S--; 6.14(m): --CH═CH--CH₂ --N⁺ E isomer; 6.7 to 6.88: Ar--H and--S--CH--C(C═N--)--N═; 7.04: --CH═CH--CH₂ --N⁺ ; 7.77 (m): --N⁺ (CH₃)₂--CH₂ --CH₂ --CH═N--O--CH₃ ; 9.57 and 9.65:--CO--NH--CH(C═O)--CH(N--)--S--.

EXAMPLE 57 The internal salt of (±)(cis)(Z) 1-[3-[7-[[(2-amino4-thiazolyl) [carboxy(3,4-dihydroxy phenyl)methoxy]imino]acetamido]2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl] 2(E)-propenyl]imidazo[1,2-a]pyrimidin-4-ium (R) or (S) or an (R+S) mixture

NMR of the proton (DMSO, 300 MHz, in ppm) 3.66 (m) masked): --S--CH₂--C(CH═CH--)═C--; 5.14 (d, resolved): --CO--NH--CH(C═O)--CH(N--)--S--;5.24 (m): --CH═CH--CH₂ --N⁺ ; 5.31 (s): Ar--CH(C═O)--O--; 5.74 (m):--CO--NH--CH(C═O)--CH(N--)--S-- cis isomerism; 6.23 (m): --CH═CH--CH₂--N⁺ E isomer; 6.65 to 6.84 (4H): Ar--H, and --S--CH--C(C═N--)--N═; 6.94(d, resolved J=16): --CH═CH--CH₂ --N⁺ ; 7.31 (sl): --NH2; 9.03 (m):mobile H's; 7.76 (dd) (1H): H in position 6 of theimidazo[1,2-a]-pyrimidin-4-ium ring; 8.39 (s): H in position 2 and 3 ofthe imidazo[ 1,2-a]-pyrimidin-4-ium ring; 9.14 (d, resolved) (1H): H inposition 7 of the imidazo-[1,2-a]pyrimidin-4-ium ring; 9.39 (d,resolved) (1H): H in position 5 of the imidazo-[1,2a]pyrimidin-4-iumring.

Unless otherwise indicated, the products of Examples 30 to 58 mentionedpreviously were prepared by the method described in Example 1, using thecorresponding nitrogenous base.

EXAMPLE 58

Preparations for injections of the following formula were prepared from500 ml of the product of Example 30 and sterile aqueous excipientsufficient for a quantity of sterile aqueous excipient sufficientquantity of 5 ml.

EXAMPLE 59

A preparation for injection was prepared containing 500 mg of theproduct of Example 2 and sterile aqueous excipient sufficient for afinal volume of 5 ml.

PHARMACOLOGICAL STUDY

In vitro activity, method of dilutions in solid medium

A series of dishes was prepared into which an equal amount of sterilenutritive medium was divided containing increasing quantities of theproduct to be studied and then each dish was seeded with severalbacterial strains. After incubation for 24 hours in an oven at 37° C.,the inhibition of growth was evaluated by the absence of any bacterialdevelopment which allowed the minimal inhibiting concentrations (MIC),expressed in micrograms and, to be determined. The results are expressedin MIC₉₀, which is the minimum concentration of antibiotic enabling theinhibitions of 90% of the strains studied in the following Table.

PHARMACOLOGICAL STUDY OF THE PROCESS OF THE INVENTION

Activity in vitro, method of dilutions in solid medium

A series of dishes are prepared in which the same quantity of sterilenutrient medium is distributed, containing increasing quantities of theproduct to be studied, then each dish is sown with several bacterialstrains.

After incubation for 24 hours in an incubator at 37° C., the growthinhibition is evaluated by the absence of any bacterial development,which allows the minimum inhibiting concentrations (MIC) expressed inmicrograms/cm³ to be determined.

The results are expressed in MIC₉₀ which is the minimum concentration ofantibiotic causing growth inhibition in 90% of the strains studied.

The following results were obtained:

    ______________________________________                                               Entero-                                                                Product                                                                              bacteries Staphylococcus     Pseudomonas                               of     Cloacae   aureus      Proteus                                                                              Aeruginosa                                Example                                                                              1321E     SG 5 11     A 235  1771 m                                    ______________________________________                                        28     0.08      0.15        0.04   0.3                                       30     0.04      0.15        0.02   0.6                                       24     0.15      0.15        0.02   0.15                                      44     0.15      0.15        0.04   0.6                                       ______________________________________                                    

    ______________________________________                                        Number of strains                                                                             Staphylo-                                                     Enterobacteria  coccus             Pseudo-                                            Cefo-   Cefo-   aureus  Proteus                                                                              monas                                  Compound                                                                              tax.S   tax.R   oxacilline S                                                                          SPP    Aeruginosa                             example 27      40      20      9      40                                     ______________________________________                                        2       0,3      5      0,6      0,15   1,25                                  4       0,3      5       1,25   0,3    5                                      9       0,6     10      1,2     0,6    2,5                                    12      0,3     10      0,6     0,3    10                                     16      0,6     10      1,2     0,6    2,5                                    17      0,6     10      1,2     0,6    1,2                                    18       0,15     2,5   0,3     0,3    2,5                                    ______________________________________                                    

Various modifications of the compounds and method of the invention maybe made without departing from the spirit of scope thereof and it shouldbe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A compound selected from the group consisting ofthe syn isomer of a compound of the formula ##STR143## in the R or Sform or in the form of an R, S mixture wherein R₁ is selected from thegroup consisting of ##STR144## in the quaternary ammonium form, R and R¹are individually selected from the group consisting of hydrogen, alkylof 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, CO₂ --Q,##STR145## CH₂ SQ, Q and Q¹ are individually hydrogen or alkyl of 1 to 4carbon atoms, R_(b) and R_(c) are individually hydrogen or acyl, A andA¹ are individually selected from the group consisting of hydrogen, anequivalent of an alkali metal, alkaline earth metal, magnesium, ammoniumand amino organic base or A and A¹ are the remainder or an easilycleavable ester group or CO₂ A is CO₂ --; and the wavy line indicatesthat CH₂ R₁ is in the E or Z position and their non-toxic,pharmaceutically acceptable acid addition salts.
 2. A compound of claim1 wherein R₁ is selected from the group consisting of ##STR146##
 3. Acompound of claim 1 wherein R₁ is selected from the group consisting of##STR147##
 4. An antibacterial composition comprising anantibactericidally effective amount of at least one compound of claim 1and an inert pharmaceutical carrier.
 5. A compound of claim 1 selectedfrom the group consisting ofa) [6R-[3(E), 60α,7β(Z)]]-2-[3-[7-[[(2-amino-4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-isoquinoliniumin the R or S form or in the form an of R, S mixture and in the form ofan internal salt or a salt with alkali metals, alkaline earth metals,magnesium, ammonia, amine organic bases, acids and its easily cleavableesters, b) [6R-[3(E),6α,7β(Z)]]-4-[3-[6,7-[[(2-amino4-thiazolyl)-[1-(3,4-dihydroxyphenyl)-2-hydroxy-2-oxoethoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-6,7dihydro-5H-pyrindinium in the R or S form or in the form of an R, Smixture and in the form of an internal salt or a salt with alkalimetals, alkaline earth metals, magnesium, ammonia, amine organic bases,acids and its easily cleavble esters.
 6. A composition of claim 4wherein an antibacterial composition comprising an antibactericidallyeffective amount of at least one compound of claim 5 and an inertpharmaceutical carrier.
 7. A method of treating bacterial infections inwarm-blooded animals comprising administering to warm-blooded animals anantibactericidally effective amount of at least one compound of claim 1.8. A method of claim 11 wherein the active compound is selected from thegroup consisting of antibactericidally effective amount of at least onecompound of claim 5 and an inert pharmaceutical carrier.
 9. Acomposition of claim 4 wherein in the compound R₁ is selected from thegroup consisting of ##STR148##
 10. A composition of claim 4 wherein inthe compound R₁ is selected from the group consisting of ##STR149## 11.A method of claim 7 wherein in the compound R₁ is selected from thegroup consisting of ##STR150##
 12. A method of claim 7 wherein thecompound R₁ is selected from the group consisting of ##STR151##